No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Exploring the full spectrum of macrophage activation
... M2 macrophages have multifaceted roles in allergic responses, parasite clearance, inflammation suppression, tissue remodelling, angiogenesis, immune regulation and tumour promotion (31). Within this subset, M2 macrophages consist of four distinct subpopulations: i) M2a, predominantly induced by IL-4 and IL-13; ii) M2b, primarily triggered by immune complexes, IL-1β and TLR ligands; iii) M2c macrophages, produced in response to IL-10, glucocorticoids and TGF-β (25,(32)(33)(34)(35)(36); and iv) M2d, primarily induced by TLR antagonists (33). The polarisation of microglia toward the M2 phenotype mirrors that of peripheral macrophages (37)(38)(39)(40), leading to distinctive mRNA profiles following stimulation with IL-4 and IL-10, including the expression of arginase 1 (Arg-1), chitinase-like protein 3, Fizz1 and peroxisome proliferator-activated receptor (PPAR) (41). ...
... However, M2b subpopulations are distinctive for high expression of IL-10 and CD86 but low production of IL-12 and Arg-1. Like M1 macrophages, they are proficient producers of IL-1, TNF-α and IL-6 (35,36). Furthermore, M2b macrophages express high levels of reactive nitrogen intermediates and iNOS (35,36). ...
... Like M1 macrophages, they are proficient producers of IL-1, TNF-α and IL-6 (35,36). Furthermore, M2b macrophages express high levels of reactive nitrogen intermediates and iNOS (35,36). ...
Macrophages form a crucial component of the innate immune system, and their activation is indispensable for various aspects of immune and inflammatory processes, tissue repair, and maintenance of the balance of the body's state. Macrophages are found in all ocular tissues, spanning from the front surface, including the cornea, to the posterior pole, represented by the choroid/sclera. The neural retina is also populated by specialised resident macrophages called microglia. The plasticity of microglia/macrophages allows them to adopt different activation states in response to changes in the tissue microenvironment. When exposed to various factors, microglia/macrophages polarise into distinct phenotypes, each exhibiting unique characteristics and roles. Furthermore, extensive research has indicated a close association between microglia/macrophage polarisation and the development and reversal of various intraocular diseases. The present article provides a review of the recent findings on the association between microglia/macrophage polarisation and ocular pathological processes (including autoimmune uveitis, optic neuritis, sympathetic ophthalmia, retinitis pigmentosa, glaucoma, proliferative vitreoretinopathy, subretinal fibrosis, uveal melanoma, ischaemic optic neuropathy, retinopathy of prematurity and choroidal neovascularization). The paradoxical role of microglia/macrophage polarisation in retinopathy of prematurity is also discussed. Several studies have shown that microglia/macrophages are involved in the pathology of ocular diseases. However, it is required to further explore the relevant mechanisms and regulatory processes. The relationship between the functional diversity displayed by microglia/macrophage polarisation and intraocular diseases may provide a new direction for the treatment of intraocular diseases.
... This leads to the destruction of the bloodbrain barrier and potentially salvageable neurones in the penumbra (Heo et al., 1999;Jayaraj et al., 2019). Infiltrating macrophages release in their proinflammatory activation state cytokines like IL-1β and IL-6, which fuel the immune response as well as oxygen and nitrogen radicals, which have a cytotoxic effect on surrounding cells (Iadecola & Anrather, 2011;Kim & Cho, 2016;Mosser & Edwards, 2008). The secretion of IFN-γ and perforin was detected as the two most important pathomechanisms of T-cells in stroke. ...
... The reason for this is a different polarization of the cells into a pro-or anti-inflammatory activation state. This is best known in macrophages, which can perform contrary functions in an M1 or M2 activation state (Boche et al., 2013;Mosser & Edwards, 2008). M1 macrophages with the capacity for immune defense develop under the influence of proinflammatory mediators, which cause them to produce proinflammatory cytokines and oxygen and nitrogen radicals. ...
... Underneath the heatmap you can see exemplary images of the infarct area for both mouse lines photographed under the fluorescence microscope. heal wounds are created by the production of interleukin-4, whereupon they produce components of the extracellular matrix to repair the injury (Boche et al., 2013;Mosser & Edwards, 2008). It is conceivable that the Y731F point mutation has led to a reduced influx of proinflammatory activated immune cells, shifting the balance toward an anti-inflammatory state. ...
Aims
To distinguish between the genuine cellular impact of the ischemic cascade by leukocytes and unspecific effects of edema and humoral components, two knock‐in mouse lines were utilized. Mouse lines Y731F and Y685F possess point mutations in VE‐cadherin, which lead to a selective inhibition of transendothelial leukocyte migration or impaired vascular permeability.
Methods
Ischemic stroke was induced by a model of middle cerebral artery occlusion. Analysis contained structural outcomes (infarct volume and extent of brain edema), functional outcomes (survival analysis, rotarod test, and neuroscore), and the extent and spatial distribution of leukocyte migration (heatmaps and fluorescence‐activated cell sorting (FACS) analysis).
Results
Inhibition of transendothelial leukocyte migration as in Y731F mice leads to smaller infarct volumes (52.33 ± 4719 vs. 70.43 ± 6483 mm³, p = .0252) and improved motor skills (rotarod test: 85.52 ± 13.24 s vs. 43.06 ± 15.32 s, p = .0285). An impaired vascular permeability as in Y685F mice showed no effect on structural or functional outcomes. Both VE‐cadherin mutations did not influence the total immune cell count or spatial distribution in ischemic brain parenchyma.
Conclusion
Selective inhibition of transendothelial leukocyte migration by VE‐cadherin mutation after ischemic stroke in a mouse model leads to smaller infarct volumes and improved motor skills.
... On the other hand, IL-10 and tumor growth factor-β (TGF-β) produced by M2 macrophages present tumor progression (35,36). It was proven that the M2 phenotype has a high capacity to facilitate tumor growth, invasion, angiogenesis, and tissue remodeling (37)(38)(39)(40). Several studies suggest that this capacity is mediated via releasing of some soluble factors (41,42). ...
... It is well documented that CD14, CD163, and CD206 as well as CXC chemokine receptor 1 (CXCR1) and CXCR2 (both chemokine receptors for CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8) usually expressed by M2 macrophages (44,45). CD163 is overexpressed in M2 macrophages; on the other hand, IL-6 and IL-13 were the well-known inducers of the expression of CD163, which contributed to the promotion of the M2 macrophage phenotype (37,39,40,46). This shifting can reduce the levels of proinflammatory cytokines, including TNF-, IL-1 , IL-6, and nitric oxide (NO) production, and can increase IL-10 levels. ...
Tumors can produce bioactive substances called tumor-derived supernatants (TDS) that modify the immune response in the host body. This can result in immunosuppressive effects that promote the growth and spread of cancer. During tumorigenesis, the exudation of these substances can disrupt the function of immune sentinels in the host and reinforce the support for cancer cell growth. Tumor cells produce cytokines, growth factors, and proteins, which contribute to the progression of the tumor and the formation of premetastatic niches. By understanding how cancer cells influence the host immune system through the secretion of these factors, we can gain new insights into cancer diagnosis and therapy.
... Notably, tumor-associated macrophages (TAMs) delineate a dynamic subpopulation, displaying a plasticity that enables phenotypic transitions contingent on TME cues [3]. The traditional dichotomy of macrophages into pro-inflammatory M1 and pro-tumoral M2 subsets has undergone a foundational shift [4][5][6]. Advances in single-cell RNA sequencing (scRNA-Seq) technologies have illuminated a more delicate macrophage spectrum, revealing overlapping transcriptional gene expression profiles between M1 and M2 entities [7][8][9]. While TAMs are conspicuously absent under normal physiological conditions, their presence in various tumors has prompted reconsideration of their classification. ...
... Our findings indicate that higher levels of M2 macrophage infiltration are linked to poorer outcomes in CRC, underscoring the pivotal role of M2 macrophages in the prognosis. Acknowledging the dual roles of M2 macrophages in immunosuppression and tumor promotion, our study involved an intersectional analysis of M2 macrophage-associated genes from the TCGA-CRC dataset with TAM marker genes derived from scRNA-seq datasets [5,6]. This integrative approach led to the discovery of 377 genes that are related to both M2 macrophages and TAMs. ...
Background
Emerging investigations have increasingly highlighted the critical role of tumor-associated macrophages (TAMs) and M2 macrophages in cancer development, progression, and metastasis, marking them as potential targets in various cancer types. The main objective of this research is to discover new biomarkers associated with TAM-M2 macrophages in colorectal cancer (CRC) and to dissect the molecular heterogeneity of CRC by combining single-cell RNA sequencing and bulk RNA-seq data.
Methods
By utilizing weighted gene co-expression network analysis (WGCNA), we acquired TAM-M2-associated genes by intersecting TAM marker genes obtained from scRNA-seq data with module genes of M2 macrophages derived from bulk RNA-seq data. We employed least absolute shrinkage and selection operator (LASSO) Cox analysis to select predictive biomarkers from these TAM-M2-related genes. Quantitative polymerase chain reaction (qPCR) was employed to validate the mRNA expression levels of the genes identified in the screening. This led to the development of the TAM-M2-related signature (TAMM2RS). We also conducted functional and immune landscape analyses of different risk groups.
Results
The combination of scRNA-seq and bulk RNA-seq analyses yielded 377 TAM-M2-related genes. DAPK1, NAGK, and TRAF1 emerged as key prognostic genes in CRC, which were identified through LASSO Cox analysis. Utilizing these genes, we constructed and validated the TAMM2RS, demonstrating its effectiveness in predicting survival in CRC patients.
Conclusion
Our research offers a thorough investigation into the molecular mechanisms associated with TAM-M2 macrophages in CRC and unveils potential therapeutic targets, offering new insights for treatment strategies in colorectal cancer.
... Numerous researches have reported that adipose tissues are endocrine organs, and their homeostasis is controlled by internal immune cells, including adipose tissue macrophages (ATMs) (8)(9)(10). Both macrophages' recruitment and polarization can regulate the microenvironment in the adipose tissues (11)(12)(13)(14). It has been clarified that the main sources of ATMs are monocyte-derived recruited macrophages as well as tissue-resident macrophages. ...
... After that, these monocytes leave the circulation and settle into the tissue, where they mature into tissue-specific macrophages. Different tissues refer to resident macrophages by different names: adipose tissue macrophages, kupffer cells in the liver, and microglial cells in the central nervous system (13). ...
Interactions between macrophages and adipocytes in adipose tissue are critical for the regulation of energy metabolism and obesity. Macrophage polarization induced by cold or other stimulations can drive metabolic reprogramming of adipocytes, browning, and thermogenesis. Accordingly, investigating the roles of macrophages and adipocytes in the maintenance of energy homeostasis is critical for the development of novel therapeutic approaches specifically targeting macrophages in metabolic disorders such as obesity. Current review outlines macrophage polarization not only regulates the release of central nervous system and inflammatory factors, but controls mitochondrial function, and other factor that induce metabolic reprogramming of adipocytes and maintain energy homeostasis. We also emphasized on how the adipocytes conversely motivate the polarization of macrophage. Exploring the interactions between adipocytes and macrophages may provide new therapeutic strategies for the management of obesity-related metabolic diseases.
... M2 macrophages are involved in wound-healing processes and primarily produce anti-inflammatory cytokines [11]. They express specific phenotype markers on their cell membrane, including mannose receptor 1 type C (CD206), macrophage scavenger receptor 1 (CD204), hemoglobin scavenger receptor (CD163), and functional markers like the MER proto-oncogene receptor tyrosine kinase (MerTK) [12]. They also release specific cytokines and chemokines, such as IL10, CC-motif chemokine ligand-17 (CCL17), CCL18, CCL22, and profibrotic growth factors like TGFβ1 [12]. ...
... They express specific phenotype markers on their cell membrane, including mannose receptor 1 type C (CD206), macrophage scavenger receptor 1 (CD204), hemoglobin scavenger receptor (CD163), and functional markers like the MER proto-oncogene receptor tyrosine kinase (MerTK) [12]. They also release specific cytokines and chemokines, such as IL10, CC-motif chemokine ligand-17 (CCL17), CCL18, CCL22, and profibrotic growth factors like TGFβ1 [12]. Among cytokines and growth factors which mediate the polarization of macrophages toward an M2 phenotype, including IL4 and IL13, tyrosine kinases, such as spleen tyrosine kinase (Syk) and phosphoinositide 3-kinase (PI3K) seems to be involved in promoting this polarized status [5]. ...
Background
Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFβ1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients.
Methods
Fourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients’ informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFβ1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFβ1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test.
Results
Cultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFβ1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFβ1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFβ1 after 24 h of treatment (p < 0.05 vs. untreated cells).
Conclusions
In cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFβ1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.
... IL-6, a versatile cytokine, exerts both proinfammatory and anti-infammatory efects, exerting infuence over a range of physiological processes encompassing immunity, tissue repair, and metabolism. IL-6 signalling can trigger the recruitment of monocytes to infammatory sites [19,22,23]. Te present study showed that, after laser treatment, the IL-6 protein concentration in the Er:YAG laser group signifcantly increased, surpassing that in the other groups. ...
... Interferon-gamma (IFN-c) is a hallmark cytokine of the T1 immune response. IFN-c produced by T1 cells is important for supporting and maintaining macrophages during chronic infection [23][24][25]. Te presence of IFN-c signifcantly amplifes the production of infammatory mediators by macrophages, thereby intensifying all of these infammatory responses. [19,24,26]. ...
Laser tattoo removal is an effective technique, but multiple rounds of treatment are required to eliminate tattoos, which can be a challenge for patients who do not have the time. Additionally, there is relatively limited research on the mechanisms of laser tattoo removal, necessitating further in-depth studies. This study aimed to investigate the efficacy of an Er:YAG laser combined with a 755-picosecond laser for tattoo removal and the changes in skin diffuse reflection, pigment particle size, macrophage recruitment, and inflammatory factor levels during combined laser treatment. Our experiments used three sets of lasers—an Er:YAG laser, a 755 nm picosecond laser, and an Er:YAG laser combined with a 755 nm picosecond laser—for tattoo removal. The effects of tattoo removal at different time points were evaluated. Moreover, the mechanisms were explored using HE staining, immunohistochemistry, diffuse reflectance measurements, in vitro gel tests, mass spectrometry, and ELISA experiments. The combined treatment was more effective for tattoo removal in rats. The combined laser treatment effectively reduced diffuse reflection from the skin, thereby increasing the effective laser power, reducing the size of the pigment particles, allowing for easier removal of the pigment, and increasing the recruitment of dermal macrophages and the release of inflammatory factors, thus increasing the rate of tattoo removal in vivo.
... Under the induction of IL-4 or IL-13, M2a macrophages mainly secrete cytokines such as IL-1Ra, TGF-β and IL-10 to promote tissue repair and ECM deposition [29]. M2b macrophages are induced by immune complexes (ICs), TLR/IL-1R ligands, secrete IL-10, IL-6, TNF-α, etc., and are thought to be associated with immune response regulation and TH2 immune response [30]. M2c macrophages are induced by IL-10 and STAT3, and can secrete a large number of anti-inflammatory cytokines such as IL-10 and TGF-β, which are mainly involved in apoptotic cell phagocytosis, tissue remodeling and matrix deposition [31]. ...
Periodontitis is a chronic inflammation caused by a bacterial infection and is intimately associated with an overactive immune response. Biomaterials are being utilized more frequently in periodontal therapy due to their designability and unique drug delivery system. However, local and systemic immune response reactions driven by the implantation of biomaterials could result in inflammation, tissue damage, and fibrosis, which could end up with the failure of the implantation. Therefore, immunological adjustment of biomaterials through precise design can reduce the host reaction while eliminating the periodontal tissue's long-term chronic inflammation response. It is important to note that macrophages are an active immune system component that can participate in the progression of periodontal disease through intricate polarization mechanisms. And modulating macrophage polarization by designing biomaterials has emerged as a new periodontal therapy technique. In this review, we discuss the role of macrophages in periodontitis and typical strategies for polarizing macrophages with biomaterials. Subsequently, we discuss the challenges and potential opportunities of using biomaterials to manipulate periodontal macrophages to facilitate periodontal regeneration.
Graphical Abstract
... Some studies show that following tissue ischaemia, macrophages contribute to tissue healing and angiogenesis (Mirza et al., 2009;Ochoa et al., 2007), while other studies show that the elevated or persistent presence of inflammatory macrophages can actually reduce myoblast proliferation, increase tissue fibrosis and induce premature myoblast differentiation (Chen et al., 2007;Miller et al., 1988). Specifically, pro-inflammatory macrophages are typically responsible for the early response and propagating the inflammatory stimulus, after which there is a transition to anti-inflammatory macrophages to resolve inflammation and contribute to tissue repair (Mosser & Edwards, 2008). Thus, timely infiltration of skeletal muscle macrophages following ligation of the femoral artery to induce hindlimb ischaemia (HLI) may be crucial to restore blood flow to the ischaemic limb via angiogenesis and arteriogenesis. ...
Skeletal muscle atrophy and dysfunction commonly accompany cardiovascular diseases such as peripheral arterial disease and may be partially attributable to systemic inflammation. We sought to determine whether acute systemic inflammation in a model of hindlimb ischaemia (HLI) could affect skeletal muscle macrophage infiltration, fibre size, or capillarization, independent of the ischaemia. Eight‐week‐old C57BL/6 male mice underwent either Sham or HLI surgery, and were killed 1, 3, or 7 days post‐surgery. Circulating inflammatory cytokine concentrations were measured, as well as immune cell infiltration and morphology of skeletal muscle from both limbs of HLI and Sham mice. In HLI compared with Sham mice at day 1, plasma interleukin‐1β levels were 216% higher (0.48 ± 0.10 vs. 0.15 ± 0.01 pg/μL, P = 0.005) and decreased by day 3. This was followed by increased macrophage presence in muscle from both ischaemic and non‐ischaemic limbs of HLI mice by day 7 (7.3‐ and 2.3‐fold greater than Sham, respectively, P < 0.0001). In HLI mice, muscle from the ischaemic limb had 21% lower fibre cross‐sectional area than the non‐ischaemic limb (724 ± 28 vs. 916 ± 46 μm², P = 0.01), but the non‐ischaemic limb of HLI mice was no different from Sham. This shows that HLI induces acute systemic inflammation accompanied by immune infiltration in both ischaemic and remote skeletal muscle; however, this did not induce skeletal muscle atrophy in remote muscle within the 7‐day time course of this study. This effect of local skeletal muscle ischaemia on the inflammatory status of remote skeletal muscle may signal a priming of muscle for subsequent atrophy over a longer time course.
Highlights
What is the central question of this study?
Does hindlimb ischaemia‐induced inflammation cause acute immune, inflammatory and morphological alterations in remote non‐ischaemic skeletal muscle?
What is the main finding and its importance?
Hindlimb ischaemia induced systemic inflammation with subsequent neutrophil and macrophage infiltration in both ischaemic and non‐ischaemic skeletal muscle; however, morphological changes did not occur in non‐ischaemic muscle within 7 days. These immune alterations may have functional implications that take longer than 7 days to manifest, and subsequent or prolonged systemic inflammation and immune infiltration of muscle could lead to morphological changes and functional decline.
... Additionally, macrophages are important regulators of tissue development, tumor growth, and wound repair. Macrophages have been termed as "M0-like" (non-polarized, "naive" state [14]), "M1-like" (inflammatory or "classically activated"), or "M2-like" (alternatively activated), but the increased sophistication of macrophage genotyping and phenotyping has shown that macrophages exist in a fluid continuum [15][16][17]. Macrophage plasticity is essential for their ability to adopt different characteristics based on the tissue location, inflammatory environment, and presence of injury-related cytokines and signaling factors. However, this phenotype plasticity causes macrophages to be a complex cell type to study due to their heterogeneity. ...
As the leading cause of mortality worldwide, cardiovascular disease (CVD) represents a variety of heart diseases and vascular disorders, including atherosclerosis, aneurysm, ischemic injury in the heart and brain, arrythmias, and heart failure. Macrophages, a diverse population of immune cells that can promote or suppress inflammation, have been increasingly recognized as a key regulator in various processes in both healthy and disease states. In healthy conditions, these cells promote the proper clearance of cellular debris, dead and dying cells, and provide a strong innate immune barrier to foreign pathogens. However, macrophages can play a detrimental role in the progression of disease as well, particularly those inflammatory in nature. This review will focus on the current knowledge regarding the role of macrophages in cardiovascular diseases.
... M1 macrophages promote inflammation. This M1-M2 transition is critical for the resolution of inflammation and tipping the balance to tissue repair [56]. 5 Additionally, an unbiased reassessment of unpublished single-cell RNA-Seq data by Jeff Biernaskie et al. revealed significant interactions between CD200 + Stmn2 + DSCs (including dermal stem cells of the dermal cup) and CD68 + F480 + peri-follicular macrophages [57]. ...
Wound healing is a complex, dynamic process involving the coordinated interaction of diverse cell types, growth factors, cytokines, and extracellular matrix components. Despite emerging evidence highlighting their importance, dermal sheath cells remain a largely overlooked aspect of wound healing research. This review explores the multifunctional roles of dermal sheath cells in various phases of wound healing, including modulating inflammation, aiding in proliferation, and contributing to extracellular matrix remodeling. Special attention is devoted to the paracrine effects of dermal sheath cells and their role in fibrosis, highlighting their potential in improving healing outcomes, especially in differentiating between hairy and non-hairy skin sites. By drawing connections between dermal sheath cells activity and wound healing outcomes, this work proposes new insights into the mechanisms of tissue regeneration and repair, marking a step forward in our understanding of wound healing processes.
... These cytokines contribute to the initiation and amplification of the inflammatory response, which lead to a polarization of Mϕ macrophages into M1 macrophages which is the form most adapted to a pro-inflammatory profile, this type of macrophage has a much stronger phagocytic capacity and pathogenic destruction activity. [37][38][39] M1 macrophages in turn, secrete high levels of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, and TNF-α, 40,41 which leads to macrophage self-activation but also to natural killer (NK) cell activation and amplification of the Th1 response. 42 To activate M0 macrophages in M1 with IFN-γ and LPS, cells switch metabolism. ...
This review article highlights the significant impact of mitochondrial dysfunction on Chagas disease (CD) cardiomyopathy. By examining the existing body of research, it provides a comprehensive anal- ysis of the detrimental consequences resulting from impaired mitochondrial function in this cardiac con- dition. We review new intricate relationship between CD cardiomyopathy, inflammatory response, mito- chondrial dysfunction and energy disbalance, elucidating some molecular mechanisms and pathways involved. This review not only enhances our understanding of the disease pathogenesis but also emphasizes the crucial role of mitochondria in cardiac function and its potential as a therapeutic target for mitigating CD cardiomyopathy.
... They are commonly classified as "M1" and "M2" macrophages. M1 macrophages, as typically described, generate pro-inflammatory cytokines with mainly antineoplastic impacts, whereas M2 macrophages produce anti-inflammatory signals that potentially accelerate tumor development [137][138][139][140]. The presence of tissueresident macrophages in PDAC is a result of their origin from embryonic hematopoiesis, and these macrophages play a crucial role in advancing the progression of tumors [141]. ...
Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.
... M1 macrophages secrete cytokines such as IL-1, TNFa, IL-6, IL-12 and matrix metalloproteinases (MMPs), while M2 cells produce arginase, TGFb, CCL18, PGE2, and IL-10 and upregulate scavenger receptors such as CD206 and CD163.64 However, in the in vivo environment, macrophage phenotype transition may exist as a continuum rather than a strict dichotomy, influenced by various signals within the microenvironment.66 Therefore, the function of macrophages undergoes precise regulation and dynamic changes in both temporal and spatial dimensions.In this study, our focus was to assess the relative distribution ofthe two predominant macrophage phenotypes, M1 and M2, at the wound site three days post-wounding. ...
Wound healing is a complex physiological process that requires precise control and modulation of many parameters. Therapeutic ion and biomolecule delivery has the capability to regulate the wound healing process beneficially. However, achieving controlled delivery through a compact device with the ability to deliver multiple therapeutic species can be a challenge. Bioelectronic devices have emerged as a promising approach for therapeutic delivery. Here, we present a pro‐reparative bioelectronic device designed to deliver ions and biomolecules for wound healing applications. The device incorporates ion pumps for the targeted delivery of H ⁺ and zolmitriptan to the wound site. In vivo studies using a mouse model further validated the device's potential for modulating the wound environment via H ⁺ delivery that decreased M1/M2 macrophage ratios. Overall, this bioelectronic ion pump demonstrates potential for accelerating wound healing via targeted and controlled delivery of therapeutic agents to wounds. Continued optimization and development of this device could not only lead to significant advancements in tissue repair and wound healing strategies but also reveal new physiological information about the dynamic wound environment.
... [22][23][24] During inflammation, monocytes migrate to the site of injury and differentiate into macrophages that polarize on a spectrum of diverse phenotypes. [25][26][27] Classically activated macrophages (M1) have been associated with the production of inflammatory cytokines and contribute to pathogenkilling at the early stages of inflammation, and the role of promoting cell proliferation and tissue remodeling have been attributed to alternatively activated macrophages (M2). 26,28 Recent studies have shown that numerical balance between M1 and M2 phenotypes over time is the main factor in biomaterial vascularization. ...
The ultimate goal of tissue engineering is to repair and regenerate damaged tissue or organ. Achieving this goal requires blood vessel networks to supply oxygen and nutrients to new forming tissues. Macrophages are part of the immune system whose behavior plays a significant role in angiogenesis and blood vessel formation. On the other hand, macrophages are versatile cells that change their behavior in response to environmental stimuli. Given that implantation of a biomaterial is followed by inflammation; therefore, we reasoned that this inflammatory condition in tissue spaces modulates the final phenotype of macrophages. Also, we hypothesized that anti‐inflammatory glucocorticoid dexamethasone improves modulating macrophages behavior. To check these concepts, we investigated the macrophages that had matured in an inflammatory media. Furthermore, we examined macrophages' behavior after maturation on a dexamethasone‐containing scaffold and analyzed how the behavioral change of maturing macrophages stimulates other macrophages in the same environment. In this study, the expression of pro‐inflammatory markers TNFa and NFκB1 along with pro‐healing markers IL‐10 and CD163 were investigated to study the behavior of macrophages. Our results showed that macrophages that were matured in the inflammatory media in vitro increase expression of IL‐10, which in turn decreased the expression of pro‐inflammatory markers TNFa and NFκB in maturing macrophages. Also, macrophages that were matured on dexamethasone‐containing scaffolds decreased the expression of IL‐10, TNFa, and NFκB and increase the expression of CD163 compared to the control group. Moreover, the modulation of anti‐inflammatory response in maturing macrophages on dexamethasone‐containing scaffold resulted in increased expression of TNFa and CD163 by other macrophages in the same media. The results obtained in this study, proposing strategies to improve healing through controlling the behavior of maturing macrophages and present a promising perspective for inflammation control using tissue engineering scaffolds.
... Proinflammatory M1 macrophages use glycolysis as the main energy source, thus inhibiting mitochondrial function. In contrast, anti-inflammatory M2 macrophages rely on oxidative phosphorylation as the major energy source, hence mitochondrial function is required for the maintenance of M2 phenotype 5 . Thus, improving the mitochondrial function may contribute to atherosclerosis regression by reprogramming mitochondrial metabolism of macrophages towards anti-inflammatory phenotype. ...
Aims
Atherosclerosis is a leading cause of morbidity and mortality in the Western countries. A growing body of evidence points to the role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Recently, it has been shown that mitochondrial hydrogen sulfide (H 2 S) can complement the bioenergetic role of Krebs cycle leading to improved mitochondrial function. However, controlled, direct delivery of H 2 S to mitochondria was not investigated as a therapeutic strategy in atherosclerosis. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with mitochondrial H 2 S donor AP39 on the development of atherosclerotic lesions in apolipoprotein E knockout (apoE -/- ) mice.
Results
Our results indicated that AP39 reduced atherosclerosis in apoE -/- mice and stabilized atherosclerotic lesions through decreased total macrophage content and increased collagen depositions. Moreover, AP39 reprogrammed macrophages from proinflammatory M1 to anti-inflammatory M2 in atherosclerotic lesions. It also upregulated pathways related to mitochondrial function, such as cellular respiration, fatty acid β-oxidation and thermogenesis while downregulated pathways associated with immune system, platelet aggregation and complement and coagulation cascades in the aorta. Furthermore, treatment with AP39 increased the expression of mitochondrial brown fat uncoupling protein 1 (UCP1) in vascular smooth muscle cells (VSMCs) in atherosclerotic lesions and upregulated mRNA expression of other thermogenesis-related genes in the aorta but not perivascular adipose tissue (PVAT) of apoE -/- mice. Finally, AP39 treatment decreased markers of activated endothelium and increased endothelial nitric oxide synthase (eNOS) expression and activation.
Conclusions
Taken together, mitochondrial H 2 S donor AP39 could provide potentially a novel therapeutic approach to the treatment/prevention of atherosclerosis.
... It was found that the infiltrated macrophages were predominantly present in the peri-strut region. The CD86 + and CD163 + macrophages largely overlapped with each other, which is in line with the high complexity of macrophage phenotypes [22]. The quantification of the area covered by the CD86 + or CD163 + macrophages and ratio of CD163 + /CD86 + show that there was no significant difference in the number of macrophages and their phenotypes among the three groups, i. e. BVS, DE-BVS, and XIENCE DES (Fig. 6B), which was consistent with the quantified inflammation score from the histopathology analyses. ...
Fully bioresorbable vascular scaffolds (BVSs) aim to overcome the limitations of metallic drug-eluting stents (DESs). However, polymer-based BVSs, such as Abbott's Absorb, the only US FDA-approved BVS, have had limited use due to increased strut thickness (157 μm for Absorb), exacerbated tissue inflammation, and increased risk of major cardiac events leading to inferior clinical performance when compared to metallic DESs. Herein we report the development of a drug-eluting BVS (DE-BVS) through the innovative use of a photopolymerizable, citrate-based biomaterial and a high-precision additive manufacturing process. BVS with a clinically relevant strut thickness of 62 μm can be produced in a high-throughput manner, i.e. one BVS per minute, and controlled release of the anti-restenosis drug everolimus can be achieved by engineering the structure of polymer coatings to fabricate drug-eluting BVS. We achieved the successful deployment of BVSs and DE-BVSs in swine coronary arteries using a custom-built balloon catheter and BVS delivery system and confirmed BVS safety and efficacy regarding maintenance of vessel patency for 28 days, observing an inflammation profile for BVS and DE-BVS that was comparable to the commercial XIENCE™ DES (Abbott Vascular).
... 17 Additionally, 8 TiME signatures (cytotoxic T lymphocyte levels, chemokines, total tumor-infiltrating lymphocyte score, T-effector score, T cell markers, gene expression profiling score, cytolytic activity score, and interferon-gamma signature) were created according to the published papers. [18][19][20][21][22] The markers of each signature are composed of several genes from the NanoString 289 panel, and the signature score for each was calculated based on the methods from those papers. ...
Background
The molecular and immunological characteristics of primary tumors and positive lymph nodes in esophageal squamous cell carcinoma (ESCC) are unknown and the relationship with recurrence is unclear, which this study attempted to explore.
Methods
A total of 30 ESCC patients with lymph node positive (IIB‐IVA) were enrolled. Among them, primary tumor and lymph node specimens were collected from each patient, and subjected to 551‐tumor‐targeted DNA sequencing and 289‐immuno‐oncology RNA panel sequencing to identify the different molecular basis and immunological features, respectively.
Results
The primary tumors exhibited a higher mutation burden than lymph nodes (p < 0.001). One‐year recurrent ESCC exhibited a higher Mucin16 (MUC16) mutation rate (p = 0.038), as well as univariate and multivariate analysis revealed that MUC16 mutation is independent genetic factor associated with reduced relapse‐free survival (univariate, HR: 5.39, 95% CI: 1.67–17.4, p = 0.005; multivariate, HR: 7.36, 95% CI: 1.79–30.23, p = 0.006). Transcriptomic results showed non‐relapse group had higher cytolytic activity (CYT) score (p = 0.025), and was enriched in the IFN‐α pathway (p = 0.036), while those in the relapsed group were enriched in the TNF‐α/NF‐κB (p = 0.001) and PI3K/Akt pathway (p = 0.014).
Conclusion
The difference in molecular characteristics between primary lesions and lymph nodes may be the cause of the inconsistent clinical outcomes. Mutations of MUC16 and poor immune infiltration are associated with rapid relapse of nodes‐positive ESCC.
... Among immune cell types exhibiting observable change in infiltrating level, M1-type macrophage gained our attention due to its pro-inflammatory and antitumor characterisms supported by previous researches, with its role as the only protective factor among immune cell types to OC according to bioinformatic analysis conducted by us. İn the early stage of TIME formation, M1-like macrophages work as tumor growth suppressor [12,13], partly by recruiting CD8 + T cell and NK cells through antigen presentation to the T-cell receptor (TCR) [14], also driving the release of chemokines (C-X-C motif chemokine ligand (CXCL) 9/10/11) derived from tumor cells to recruit NK cells [15]. The characteristic of pyroptosis about promoting antigenic substance release (from tumor cells) may induce an inflammatory response driven by M1 macrophages. ...
Ovarian cancer has the highest mortality among gynecological malignancies, and exploring effective strategies to reverse the immunosuppressive tumor microenvironment in patients remains a pressing scientific challenge. In this study, we identified a pyroptosis-related protective factor, GBP5, which significantly inhibits the growth of ovarian cancer cells and patient-derived ovarian cancer organoids, impeding the invasion and migration of ovarian cancer cells. Results of immunohistochemistry and external single-cell data verification were consistent. Further research confirmed that GBP5 in ovarian cancer cell can induce canonical pyroptosis through JAK2/STAT1 pathway, thereby restraining the progression of ovarian cancer. Interestingly, in this study, we also discovered that ovarian cancer cells with high GBP5 expression exhibit increased expressions of CXCL9/10/11 in a co-culture assay. Subsequent immune cell infiltration analyses revealed the remodeling of immunosuppressive microenvironment in ovarian cancer patients, characterized by increased infiltration and polarization of M1 macrophages. External immunotherapy database analysis showed profound potential for the application of GBP5 in immunotherapy strategies for ovarian cancer. Overall, our study demonstrates that the protective factor GBP5 significantly inhibits ovarian cancer progression, triggering canonical pyroptosis through the JAK2-STAT1 pathway. Driven by its pro-inflammatory nature, it can also enhance M1 macrophages polarization and reverse immunosuppressive microenvironment, thus providing new insights for ovarian cancer treatment.
... In response to tissue injury, monocytes are rapidly recruited to the injury site and undergo differentiation into macrophages [8]. These macrophages exhibit remarkable plasticity, allowing them to respond effectively to environmental signals and adjust their phenotype accordingly [9]. Typically, within approximately one week after injury, macrophages display a pro-inflammatory phenotype (M1), aiding in the clearance of damage-associated and pathogen-associated molecular patterns. ...
Effective tissue repair relies on the orchestration of different macrophage phenotypes, both the M2 phenotype (promotes tissue repair) and M1 phenotype (pro-inflammatory) deserve attention. In this study, we propose a sequential immune activation strategy to mediate bone regeneration, by loading lipopolysaccharide (LPS) onto the surface of a strontium (Sr) ions -contained composite scaffold, which was fabricated by combining Sr-doped micro/nano-hydroxyapatite (HA) and dual degradable matrices of polycaprolactone (PCL) and poly (lactic-co-glycolic acid) (PLGA). Our strategy involves the sequential release of LPS to promote macrophage homing and induce the expression of the pro-inflammatory M1 phenotype, followed by the release of Sr ions to suppress inflammation. In vitro and in vivo experiments demonstrated that, the appropriate pro-inflammatory effects at the initial stage of implantation, along with the anti-inflammatory effects at the later stage, as well as the structural stability of the scaffolds conferred by the composition, can synergistically promote the regeneration and repair of bone defects.
... Activated macrophages are generally classified into two broad categories, often referred to as classically activated M1 macrophages and alternately activated M2 macrophages [13,111]. Depending on the activating stimulus received, M2 macrophages can be further divided into four distinct subgroups: M2a, M2b, M2c, and M2d [112,113]. This phenomenon of two different M1/M2 phenotypes is known as "macrophage polarization" (Fig. 4). ...
As a natural immune cell and antigen presenting cell, macrophages have been studied and engineered to treat human diseases. Macrophages are well-suited for use as drug carriers because of their biological characteristics, such as excellent biocompatibility, long circulation, intrinsic inflammatory homing and phagocytosis. Meanwhile, macrophages’ uniquely high plasticity and easy re-education polarization facilitates their use as part of efficacious therapeutics for the treatment of inflammatory diseases or tumors. Although recent studies have demonstrated promising advances in macrophage-based drug delivery, several challenges currently hinder further improvement of therapeutic effect and clinical application. This article focuses on the main challenges of utilizing macrophage-based drug delivery, from the selection of macrophage sources, drug loading, and maintenance of macrophage phenotypes, to drug migration and release at target sites. In addition, corresponding strategies and insights related to these challenges are described. Finally, we also provide perspective on shortcomings on the road to clinical translation and production.
... The top features identified when contrasting Clusters 11 and 3 were then used to generate a heatmap to evaluate how the expression of these features varied across all macrophage clusters (Fig. 5g). Findings from the analysis suggested that there is a spectrum of macrophage phenotypes, which is consistent with human macrophage literature 39 . As such, we next sought to better define the heterogeneity of the macrophage populations without relying on predefined cell type gene signatures. ...
Osteosarcoma (OS) is a heterogeneous, aggressive malignancy of the bone that disproportionally affects children and adolescents. Therapeutic interventions for OS are limited, which is in part due to the complex tumor microenvironment (TME). As such, we used single-cell RNA sequencing (scRNA-seq) to describe the cellular and molecular composition of the TME in 6 treatment-naïve dogs with spontaneously occurring primary OS. Through analysis of 35,310 cells, we identified 41 transcriptomically distinct cell types including the characterization of follicular helper T cells, mature regulatory dendritic cells (mregDCs), and 8 tumor-associated macrophage (TAM) populations. Cell-cell interaction analysis predicted that mregDCs and TAMs play key roles in modulating T cell mediated immunity. Furthermore, we completed cross-species cell type gene signature homology analysis and found a high degree of similarity between human and canine OS. The data presented here act as a roadmap of canine OS which can be applied to advance translational immuno-oncology research.
... 120,121 While TAMs with a type 1 macrophage phenotype are traditionally pro-inflammatory and can eradicate organisms, TAMs expressing the M2 phenotype are immunosuppressive in nature. 122 Predominance of the M2 phenotype in the tumour microenvironment has been associated with worse prognosis in IDH-wt glioblastoma. [123][124][125][126] Generally, glioblastomas exhibit a limited presence of tumour-infiltrating lymphocytes. ...
In the dynamic landscape of glioblastoma, the 2021 World Health Organization Classification of Central Nervous System tumours endeavoured to establish biological homogeneity, yet isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma persists as a tapestry of clinical and molecular diversity. Intertumoural heterogeneity in IDH-wt glioblastoma presents a formidable challenge in treatment strategies. Recent strides in genetics and molecular biology have enhanced diagnostic precision, revealing distinct subtypes and invasive patterns that influence survival in patients with IDH-wt glioblastoma. Genetic and molecular biomarkers, such as the overexpression of neurofibromin 1, phosphatase and tensin homolog and/or cyclin-dependent kinase inhibitor 2A, along with specific immune cell abundance and neurotransmitters, correlate with favourable outcomes. Conversely, increased expression of epidermal growth factor receptor tyrosine kinase, platelet-derived growth factor receptor alpha and/or vascular endothelial growth factor receptor, coupled with the prevalence of glioma stem cells, tumour-associated myeloid cells, regulatory T cells and exhausted effector cells, signifies an unfavourable prognosis. The methylation status of O6-methylguanine–DNA methyltransferase and the influence of microenvironmental factors and neurotransmitters further shape treatment responses. Understanding intertumoural heterogeneity is complemented by insights into intratumoural dynamics and cellular interactions within the tumour microenvironment. Glioma stem cells and immune cell composition significantly impact progression and outcomes, emphasizing the need for personalized therapies targeting pro-tumoural signalling pathways and resistance mechanisms. A successful glioblastoma management demands biomarker identification, combination therapies and a nuanced approach considering intratumoural variability. These advancements herald a transformative era in glioblastoma comprehension and treatment.
... M1-type macrophages mediate inflammatory responses, while M2-type macrophages promote tissue repair and suppression. Regulatory macrophages are responsible for secreting IL-10, and myeloid-derived suppressor cells (MDSCs) contribute to tumor development (Mosser and Edwards, 2008). It is important to note that these macrophage subtypes undergo transdifferentiation and regulation throughout the progression of tumors (Biswas and Mantovani, 2010). ...
Since its identification as a marker for advanced melanoma in the 1980s, CD146 has been found to have multiple functions in both physiological and pathological processes, including embryonic development, tissue repair and regeneration, tumor progression, fibrosis disease, and inflammations. Subsequent research has revealed that CD146 is involved in various signaling pathways as a receptor or co-receptor in these processes. This correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis, prognosis, and targeted therapy. To better comprehend the versatile roles of CD146, we have summarized its research history and synthesized findings from numerous reports, proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development, regeneration, and various diseases. Targeting CD146 would consequently halt cell state shifting during the onset and progression of these related diseases. Therefore, the development of therapy targeting CD146 holds significant practical value.
... They exhibit high plasticity and become either proinflammatory or anti-inflammatory. In vitro-generated proinflammatory macrophages are called M1, while anti-inflammatory macrophages are called M2 [4,5]. M1 macrophages have been characterized by high expression of MHC class II molecules, CD86 and CD274 (PD-L1), secretion of proinflammatory cytokines, such as IL-1, IL-6, TNF, IL-12, IL-23, and IL-18, and production of NO. ...
Tumor‐associated macrophages (TAM) are abundant in several tumor types and usually correlate with poor prognosis. Previously, we demonstrated that anti‐inflammatory macrophages (M2) inhibit NK cell effector functions. Here, we explored the impact of TAM on NK cells in the context of clear‐cell renal cell carcinoma (ccRCC). Bioinformatics analysis revealed that an exhausted NK cell signature strongly correlated with an M2 signature. Analysis of TAM from human ccRCC samples confirmed that they exhibited an M2‐skewed phenotype and inhibited IFN‐γ production by NK cells. Moreover, human M0 macrophages cultured with conditioned media from ccRCC cell lines generated macrophages with an M2‐skewed phenotype (TAM‐like), which alike TAM, displayed suppressive activity on NK cells. Moreover, TAM depletion in the mouse Renca ccRCC model resulted in delayed tumor growth and reduced volume, accompanied by an increased frequency of IFN‐γ‐producing tumor‐infiltrating NK cells that displayed heightened expression of T‐bet and NKG2D and reduced expression of the exhaustion‐associated co‐inhibitory molecules PD‐1 and TIM‐3. Therefore, in ccRCC, the tumor microenvironment polarizes TAM toward an immunosuppressive profile that promotes tumor‐infiltrating NK cell dysfunction, contributing to tumor progression. In addition, immunotherapy strategies targeting TAM may result in NK cell reinvigoration, thereby counteracting tumor progression.
... By contrast, 'alternatively-activated' M2 macrophages are characterized by the production of type II cytokines, such as IL-4, IL-6 and IL-10, which promote anti-in ammatory responses. These M2 macrophages also possess protumorigenic functions (5)(6)(7)(8). In general, both M1-like and M2-like phenotypes can be present within the same microenvironment. ...
Gastric cancer, the most frequently diagnosed type of primary cancers, is associated with a high mortality rate, and imposes a significant burden on patients and society. Recent studies have found that the kallikrein-binding protein kallistatin (KS) is involved in cancer progression. However, the effects of KS on macrophages in the immune microenvironment of gastric cancer remains elusive. In the present study, we found that overexpression of KS could enhance macrophages to engulf gastric cells in vitro . We also identified that, through immunohistochemical analysis, there was an increase in CD24 expression in gastric cancer, which was associated with unfavorable prognoses. Next, it was revealed that KS overexpression could downregulate the expression of CD24 by Sanger sequencing. In vitro experiments revealed that KS overexpression resulted in the inhibition of the hypoxia-inducible factor (HIF)-1α signaling pathway, as well as decreased expression of CD24. HIF-1α downregulation also decreased the transcription and expression of CD24 in vitro , with a magnitude similar to that seen upon KS overexpression. Furthermore, activation of AKT-HIF-1α reversed the inhibitory effect of KS overexpression, restoring the transcription and expression of CD24. Collectively, KS decreases CD24 expression via the AKT-HIF-1α pathway, altering the anti-phagocytic pattern of gastric cancer cells towards tumor-associated macrophages and strengthening innate immunity, thereby influencing the prognosis of gastric cancer. In summary, our findings have identified KS as a novel factor in the pathway that reduces CD24 expression, thus contributing to a deeper understanding of the mechanisms involved in tumor immune evasion and supplying a potential drug for gastric cancer immunotherapy.
... Nevertheless, there are still several challenges that need to be addressed in order to successfully translate these advancements into clinical settings. It is important to carefully address and resolve concerns related to the source of cells, manufacturing costs, and the fate of the cell carriers within the body [8]. These factors must be thoroughly considered to ensure the successful application of cell-based drug delivery techniques. ...
Cells have emerged as highly promising vehicles for delivering drugs due to their unique advantages. They have the ability to bypass immune recognition, navigate biological barriers, and reach difficult-to-access tissues through sensing and active movement. Over the past couple of decades, extensive research has been conducted to understand how cell carriers can overcome biological barriers and influence drug effectiveness. This has resulted in the development of engineered cells for targeted drug delivery to specific tissues. Despite the presence of exciting developments, a comprehensive understanding of the challenges and potential strategies is necessary for the effective clinical application of cell-based drug carriers. This review provides an overview of recent progress and novel concepts in cell-based drug carriers, as well as their potential for translation into clinical practice. Additionally, we delve into important factors and emerging strategies for designing the next generation of cell-based delivery technologies, with a particular emphasis on achieving greater accuracy and targeted drug administration.
... C. Xu et al. phenotypes, including pro-inflammatory M1 and anti-inflammatory M2 phenotypes [57,58], and GPR37 is a key regulator of macrophage phenotypes. Macrophages expressing GPR37 exhibit an anti-inflammatory M2 phenotype, producing lower levels of IL-1β and higher levels of IL-10 and TGFβ, suggesting that GPR37 is an important mediator of inflammation and immune regulation [54]. ...
G protein-coupled receptors (GPCRs), which form the largest family of membrane protein receptors in humans, are highly complex signaling systems with intricate structures and dynamic conformations and locations. Among these receptors, a specific subset is referred to as orphan GPCRs (oGPCRs) and has garnered significant interest in pain research due to their role in both central and peripheral nervous system function. The diversity of GPCR functions is attributed to multiple factors, including allosteric modulators, signaling bias, oligomerization, constitutive signaling, and compartmentalized signaling. This review primarily focuses on the recent advances in oGPCR research on pain mechanisms, discussing the role of specific oGPCRs including GPR34, GPR37, GPR65, GPR83, GPR84, GPR85, GPR132, GPR151, GPR160, GPR171, GPR177, and GPR183. The orphan receptors among these receptors associated with central nervous system diseases are also briefly described. Understanding the functions of these oGPCRs can contribute not only to a deeper understanding of pain mechanisms but also offer a reference for discovering new targets for pain treatment.
... 23 Some studies have proposed that latent intracellular mycobacteria infection can raise a dysfunction of macrophages, resulting in persistent and excessive activation of inflammatory immunity. 24,25 The aforementioned processes are pivotal in the airway remodeling process that leads to chronic airflow obstruction. 26 Age is often listed as a risk factor for COPD because there is a physiologic decline in lung function with age. ...
Background
Prior pulmonary tuberculosis (PTB) might be associated with the development of chronic obstructive pulmonary disease (COPD). However, the impact of prior PTB on the risk of incident COPD has not been studied in a large prospective cohort study of the European population.
Objectives
This study aimed to investigate the association of prior PTB with the risk of COPD.
Design
Prospective cohort study.
Methods
A multivariable Cox proportional model was used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) for the association of prior PTB with COPD. Subgroup analyses were further conducted among individuals stratified by age, sex, body mass index, smoking status, drinking status, physical activity, and polygenic risk score (PRS).
Results
The study involved a total of 216,130 participants, with a median follow-up period of 12.6 years and 2788 incident cases of COPD. Individuals with a prior history of PTB at baseline had an 87% higher risk of developing incident COPD compared to those without such history [adjusted hazard ratio (aHR) = 1.87; 95% confidence interval (CI): 1.26–2.77; p = 0.002]. Subgroup analysis revealed that individuals having prior PTB history presented a higher risk of incident COPD among individuals who were aged from 50 to 59 years with aHR of 2.47 (1.02–5.95, p = 0.044), older than 59 years with aHR of 1.81 (1.16–2.81, p = 0.008), male with aHR of 2.37 (1.47–3.83, p < 0.001), obesity with aHR of 3.35 (2.16–5.82, p < 0.001), previous smoking with aHR of 2.27 (1.39–3.72, p < 0.001), current drinking with aHR of 1.98 (1.47–3.83, p < 0.001), low physical activity with aHR of 2.62 (1.30–5.26, p = 0.007), and low PRS with aHR of 3.24 (1.61–6.53, p < 0.001), as well as high PRS with aHR of 2.43 (1.15–5.14, p = 0.019).
Conclusion
A history of PTB is an important independent risk factor for COPD. Clinical staff should be aware of this risk factor in patients with prior PTB, particularly in countries or regions with high burdens of PTB.
... Macrophages are large phagocytic cells distributed in all tissues with diverse functions (1)(2)(3). As phagocytes, macrophages engulf and degrade threatening pathogens, cellular debris and damaged extracellular matrix material, called phagocytosis. ...
Macrophage phagocytosis is critical for the immune response, homeostasis regulation and tissue repair. This intricate process involves complex changes in cell morphology, cytoskeletal reorganization, and various receptor-ligand interactions controlled by mechanical constraints. However, there is a lack of comprehensive theoretical and computational models that investigate the mechanical process of phagocytosis in the context of cytoskeletal rearrangement. To address this issue, we propose a novel coarse-grained mesoscopic model that integrates a fluid-like cell membrane and a cytoskeletal network to study the dynamic phagocytosis process. The growth of actin filaments results in the formation of long and thin pseudopods, and the initial cytoskeleton can be disassembled upon target entry and reconstructed after phagocytosis. Through dynamic changes in the cytoskeleton, our macrophage model achieves active phagocytosis by forming a phagocytic cup utilizing pseudopods in two distinct ways. We have developed a new algorithm for modifying membrane area in order to prevent membrane rupture and ensure sufficient surface area during phagocytosis. Additionally, the bending modulus, shear stiffness, and cortical tension of the macrophage model are investigated through computation of the axial force for the tubular structure and micropipette aspiration. With this model, we simulate active phagocytosis at the cytoskeletal level and investigate the mechanical process during the dynamic interplay between macrophage and target particles.
... Additionally, post-transcriptional mechanisms intricately modulate the response to innate immune signaling and/ or the polarization in myeloid cells and other cell types. Upon the proinflammatory stimulation, macrophages undergo the polarization into the classically activated phenotype with proinflammatory properties [67]. During this polarization, METTL3 has been shown to be upregulated, which further promotes the proinflammatory phenotype [68]. ...
Inflammation orchestrates a finely balanced process crucial for microorganism elimination and tissue injury protection. A multitude of immune and non-immune cells, alongside various proinflammatory cytokines and chemokines, collectively regulate this response. Central to this regulation is post-transcriptional control, governing gene expression at the mRNA level. RNA-binding proteins such as tristetraprolin, Roquin, and the Regnase family, along with RNA modifications, intricately dictate the mRNA decay of pivotal mediators and regulators in the inflammatory response. Dysregulated activity of these factors has been implicated in numerous human inflammatory diseases, underscoring the significance of post-transcriptional regulation. The increasing focus on targeting these mechanisms presents a promising therapeutic strategy for inflammatory and autoimmune diseases. This review offers an extensive overview of post-transcriptional regulation mechanisms during inflammatory responses, delving into recent advancements, their implications in human diseases, and the strides made in therapeutic exploitation.
... During cellular apoptosis, phosphatidylserine (PS) translocates to the outer membrane, serving as a crucial 'eat-me' signal that recruits mononuclear macrophages to engulf and clear apoptotic cells. This process mediates thrombus resolution [37]. When monocytes are attracted to the vascular endothelium by chemotactic factors like monocyte chemotactic protein-1 (MCP-1), they differentiate into macrophages, exerting either pro-inflammatory or anti-inflammatory effects. ...
Background
Despite reports of pulmonary embolism (PE) as a major adverse effect of Crizotinib, the underlying mechanisms remain unclear. This study investigated the pro-thrombotic effects of Crizotinib in mice and its cellular impact.
Methods
Mice underwent inferior vena cava(IVC )ligation or carrageenan-induced tail thrombosis with Crizotinib treatment. Thrombosis incidence and pathology were assessed. In vitro, Crizotinib's effects on human umbilical vein endothelial cell (HUVEC) survival, apoptosis, and permeability, and macrophage polarization and phagocytosis were evaluated.
Results
Crizotinib can cause IVC thrombosis in mice undergoing laparotomy sham surgery. In the Balb/c mouse IVC and tail thrombosis model induced with carrageenan injection, Crizotinib demonstrated an inflammation-independent thrombopromoting effect. In vivo studies in different strains of mice at an ambient temperature of 18°C (but not 25°C) confirmed that Crizotinib has the effect of promoting IVC thrombosis and PE. Mechanistically, Crizotinib induced HUVEC apoptosis and decreased their survival, compromising the endothelial barrier. Additionally, Crizotinib inhibited macrophage polarization and phagocytosis.
Conclusion
Crizotinib significantly increases thrombosis in mice, likely due to its detrimental effects on endothelial barrier integrity and macrophage function, highlighting potential mechanisms for its clinical association with PE.
... Taken together, this data indicates that while SOCS1 KIR dimer and SOCS1 KIR both attenuated TLR7-induced in ammatory genes, the SOCS1 KIR dimer demonstrated a higher attenuation e cacy, particularly in primary macrophages. SOCS1 KIR mimetics attenuate STAT1 transcriptional activity IFNγ canonically signals through JAK2-mediated phosphorylation of STAT1 and is also a potent activator of macrophage effector functions such as phagocytosis, antigen presentation, and NO synthesis (55)(56)(57). SOCS1 KIR has been previously shown to bind JAK2 and attenuate STAT1 activation (46, 58) however, the regulation of downstream transcriptional activity by both the monomeric and dimeric variants remains poorly understood. To better understand the effects of the SOCS1 mimetics on STAT1 transcriptional activity, we utilized a HeLa-reporter cell line transfected with a STAT1 responsive luciferase construct. ...
Although it is known that SOCS1 can modulate JAK/STAT signaling through both its kinase inhibitory region (KIR) and SOCS box domain, and limit toll-like receptor (TLR) induced inflammation via the SOCS1 box domain, the relative contribution of the KIR domain to TLR regulation is not well understood. In this study, we utilized peptide mimics of SOCS1 KIR to study the effect of the KIR domain in modulating TLR7 and interferon γ (IFNγ) signaling in murine primary macrophages and cell lines. We found that SOCS1 KIR mimetics were able to inhibit, by up to 50%, the inflammatory signatures associated with TLR7 stimulation, IFNγ stimulation, and the enhanced IFNγ-induced gene signature, mediated by TLR7 and IFNγ co-treatment. While inhibition of IFNg mediated activation correlated with reduced Y701 phosphorylation on STAT1 and Y705 phosphorylation on STAT3, the inhibition of TLR7-induced inflammation and the TLR7-enhanced IFNγ-induced gene signature coincided with a reduction in both Y701 and S727 phosphorylation on the STAT1 transactivation domain. Altogether, we report for the first time a novel role of the SOCS1 KIR domain in regulating TLR7-mediated, and TLR7-enhanced IFNγ-mediated, inflammation.
... This aligns with prior reports highlighting the direct role of CD8 T cells in tumor cell killing and their pivotal role in determining the response to ICIs [31]. Additionally, Macrophage M1 cells are recognized as crucial tumor suppressor cells associated with T cell stimulation and ICI therapy [32,33]. ...
Enhancing cancer treatment efficacy remains a significant challenge in human health. Immunotherapy has witnessed considerable success in recent years as a treatment for tumors. However, due to the heterogeneity of diseases, only a fraction of patients exhibit a positive response to immune checkpoint inhibitor (ICI) therapy. Various single-gene-based biomarkers and tumor mutational burden (TMB) have been proposed for predicting clinical responses to ICI; however, their predictive ability is limited. We propose the utilization of the Text Graph Convolutional Network (GCN) method to comprehensively assess the impact of multiple genes, aiming to improve the predictive capability for ICI response. We developed TG468, a Text GCN model framing drug response prediction as a text classification task. By combining natural language processing (NLP) and graph neural network techniques, TG468 effectively handles sparse and high-dimensional exome sequencing data. As a result, TG468 can distinguish survival time for patients who received ICI therapy and outperforms single gene biomarkers, TMB and some classical machine learning models. Additionally, TG468’s prediction results facilitate the identification of immune status differences among specific patient types in the Cancer Genome Atlas dataset, providing a rationale for the model’s predictions. Our approach represents a pioneering use of a GCN model to analyze exome data in patients undergoing ICI therapy and offers inspiration for future research using NLP technology to analyze exome sequencing data.
... Macrophages are also key players in the innate immune system and are remarkable phagocytic cells. They clear cellular debris, immune complexes, apoptotic cells and engulf bacteria, but they also have a role in wound healing and immune regulation [171]. Activated macrophages are sub-classified into M1 and M2 with distinct functions in an immune response. ...
... They clear apoptotic cells (including neutrophils), replacing them as the primary inflammatory mediator and initiating the transition out of the inflammatory phase. These macrophages, as they phagocytose the apoptotic cells, transition to a reparative state that stimulates keratinocytes, fibroblasts, and angiogenesis to promote tissue regeneration [7][8][9]. Macrophages also play a role in the release of proinflammatory cytokines that recruit and activate additional leukocytes early in the inflammatory phase [7]; later in the inflammatory phase, they also enhance their anti-inflammatory role by releasing growth factors that promote re-epithelialization, fibroplasia, and angiogenesis [4]. ...
Healing wounds is an important physiological process in the body followed by trauma, burn injuries, post-surgery complications or different diseases that can damage the skin and tissues. Millions of people struggle with their healing process every year and some of them pass away according to the World Health Organization (WHO). Wound healing is done by different processes that are divided into hemostasis/inflammation phase, proliferation phase, and remodeling phase. The pathophysiology of these processes and the factors affecting them is explained. There are two general factors including systemic and local factors contributing, both explained in this research. Many resources have been reviewed regarding the factors that can enhance the healing process. All the information collected to fulfill one of the important purposes of this research. The enhancing factors which are discussed include therapeutic strategies for enhancing angiogenesis in wound healing like using growth Factors, Non-Growth Factor Protein Delivery, gene, and nucleic Acid-Based therapies for wound angiogenesis. Stem cells therapy one of the most recent topics that is being researched a lot in the wound healing subject and potentially gives hopes to healing enhancement, although more clinical trial and experiments need to be done especially on the human body to be able to get more specific results, hopefully can be proved and used to benefit the people who suffer from this problem around the world.
... S8 Macrophages also release the cytokines IGF-1, tumour necrosis factor alpha, IL-1β, and interferon gamma. 82 However, whether the above macrophage-derived cytokines contribute to exercise-induced muscle adaptation remains unknown. The chemokine family consists of~50 endogenous chemokine ligands in humans that play critical roles in haematopoiesis and immune cell homeostasis by controlling cell migration and cell positioning. ...
Exercise is recognized to play an observable role in improving human health, especially in promoting muscle hypertrophy and intervening in muscle mass loss‐related diseases, including sarcopenia. Recent rapid advances have demonstrated that exercise induces the release of abundant cytokines from several tissues (e.g., liver, muscle, and adipose tissue), and multiple cytokines improve the functions or expand the numbers of adult stem cells, providing candidate cytokines for alleviating a wide range of diseases. Muscle satellite cells (SCs) are a population of muscle stem cells that are mitotically quiescent but exit from the dormancy state to become activated in response to physical stimuli, after which SCs undergo asymmetric divisions to generate new SCs (stem cell pool maintenance) and commit to later differentiation into myocytes (skeletal muscle replenishment). SCs are essential for the postnatal growth, maintenance, and regeneration of skeletal muscle. Emerging evidence reveals that exercise regulates muscle function largely via the exercise‐induced cytokines that govern SC potential, but this phenomenon is complicated and confusing. This review provides a comprehensive integrative overview of the identified exercise‐induced cytokines and the roles of these cytokines in SC function, providing a more complete picture regarding the mechanism of SC homeostasis and rejuvenation therapies for skeletal muscle.
... Adipose tissues, composed of adipocytes, preadipocytes, endothelial cells, and immune cells (including macrophage and lymphocytes), are essential initiators of the inflammatory response. Studies have shown that CD11c-activated adipose tissue macrophage (ATMs) derived from obese mice exhibit overlapping profiles and increased transcription of related genes in M1/M2 macrophage [62,63]. During the development of obesity, adipose tissues exhibit elevated macrophage infiltration, with a predilection for pro-inflammatory M1 activation as opposed to the M2 phenotype in lean patients [64]. ...
... Monocytes play a central role in host defense by engulfing pathogens, presenting antigens to immune cells and producing numerous inflammatory mediators [1]. Pro-inflammatory cytokines are important mediators in immune regulation and are produced during immune and host defense response [2][3][4]. Interleukin 1 alpha (IL-1α) is recognized as a central mediator of inflammation, produced mainly by activated macrophages [5]. IL-1α has a wide range of target cells such as fibroblasts, endothelial cells, mature T cells, mature B cells, monocytes and neutrophils (induces secretion of several cytokines, including Interleukin 8 (IL-8) and IL-1 itself). ...
Peripheral blood mononuclear cells were stimulated with lipopolysaccharide and incubated at different temperatures (34, 37 and 39 oC). Interleukin-1 alpha (IL-1α) was measured. Phagocytic activity of LPS-stimulated monocytes in terms of bacterial uptake and intracellular bacterial killing was checked at different temperatures and time intervals in vitro. Early elevation IL-1α was found in LPS-stimulated monocytes that incubated at 39 oC followed by cells that incubated at 37 oC and lowest level was detected at 34 oC. Similar trend was reported in the phagocytic activity in terms of bacterial uptake and intracellular bacterial killing. The sharp decrease in IL-1α was observed 12 h post exposure to LPS in LPS-stimulated monocytes that incubated at 39 oC only. While, the decrease of IL-1α levels in other incubated temperatures (34 and 37 oC) was seen later than incubated at 39 oC. This report describes the striking effect of incubation temperature on activity of LPS-stimulated monocytes. This result explains clearly the important role of elevation temperature in modulating the immune response against external pathogens.
... The typical polarity of macrophages is often defined as M1 and M2 macrophages to understand their diversity and plasticity [30]. The cytokines such as IL-4 and IL-13 produced by type 2 T helper (Th2) cells, a subset of Th cells in CD4 + T cells, are known to induce M2 macrophage polarization [31]. ...
Background
Severe peripheral nerve damage always requires surgical treatment. Autologous nerve transplantation is a standard treatment, but it is not sufficient due to length limitations and extended surgical time. Even with the available artificial nerves, there is still large room for improvement in their therapeutic effects. Novel treatments for peripheral nerve injury are greatly expected.
Methods
Using a specialized microfluidic device, we generated artificial neurite bundles from human iPSC-derived motor and sensory nerve organoids. We developed a new technology to isolate cell-free neurite bundles from spheroids. Transplantation therapy was carried out for large nerve defects in rat sciatic nerve with novel artificial nerve conduit filled with lineally assembled sets of human neurite bundles. Quantitative comparisons were performed over time to search for the artificial nerve with the therapeutic effect, evaluating the recovery of motor and sensory functions and histological regeneration. In addition, a multidimensional unbiased gene expression profiling was carried out by using next-generation sequencing.
Result
After transplantation, the neurite bundle-derived artificial nerves exerted significant therapeutic effects, both functionally and histologically. Remarkably, therapeutic efficacy was achieved without immunosuppression, even in xenotransplantation. Transplanted neurite bundles fully dissolved after several weeks, with no tumor formation or cell proliferation, confirming their biosafety. Posttransplant gene expression analysis highlighted the immune system’s role in recovery.
Conclusion
The combination of newly developed microfluidic devices and iPSC technology enables the preparation of artificial nerves from organoid-derived neurite bundles in advance for future treatment of peripheral nerve injury patients. A promising, safe, and effective peripheral nerve treatment is now ready for clinical application.
... 12 And a diverse spectrum of phenotypes between classically activated (Type 1, "pro-inflammatory", M1) and alternatively activated (Type 2, "pro-healing", M2) are exhibited in macrophages, the cells FBGCs originate from. 20 Based on these observations, a re-examination of the role of FBGCs in the FBR and their phenotypic diversity is necessary. PTFE grafts as the control, we observed that healing is limited to several millimeters within the anastomosis in PTFE grafts, confirming the relevance of the model to human. ...
The 70-year quest for synthetic vascular graft (sVG) endothelialization has not led to completely healed endothelium in clinically used sVGs. In humans, healing is limited to the vicinity of anastomotic regions (pannus ingrowth) and does not reach the middle regions of sVGs. Here, we conducted proof-of-concept implantation of immunomodulatory porous regenerative scaffolds for in situ vascular engineering (IMPRESSIVE) as interposition grafts in sheep carotid arteries. These scaffolds are based on a new polyurethane (PU) material featuring a 40 micron precision porous structure optimized for angiogenesis. The modulus of the PU was adjusted to match that of natural arteries. The implantation study revealed rapid healing in IMPRESSIVE sVGs. In side-by-side comparison with standard polytetrafluoroethylene (PTFE) grafts, the luminal surfaces of PU grafts were almost completely covered with nucleated cells, while healing in PTFE grafts was limited to several millimeters within anastomotic regions. Endothelialization was observed in the middle regions of PU grafts and overall endothelialization increased significantly compared to PTFE grafts. Densities of mononuclear cells, foreign body giant cells (FBGCs), and endothelial cells within graft walls of PU grafts were also significantly higher than those in PTFE grafts, suggesting transmural cellular infiltration may play a key role in overall improved healing. High percentages of macrophages in pores of PU grafts show Type 1 (CCR7+) and Type 2 (mannose receptor, MR+) characteristics. We also discovered that FBGCs exist in a diverse spectrum of phenotypes. Dually activated FBGCs (CCR7+MR+, G1/2) dominate the population of FBGCs associated with pro-healing PU grafts. These observations suggest a complex, balanced pro-healing response from macrophages and FBGCs. The IMPRESSIVE approach may enable complete endothelialization in pro-healing sVGs and have wide applications in implantable devices and tissue engineering.
Patients with end-stage kidney disease (ESKD) are at high risk of severe COVID-19. We performed longitudinal single cell multi-omic immune profiling of ESKD patients with COVID-19, sampled during two waves of the pandemic. Uniquely, for a subset of patients, we obtained samples before and during acute infection, allowing intra-individual comparison. Using single-cell transcriptome, surface proteome and immunoreceptor sequencing of 580,040 high-quality cells, derived from 187 longitudinal samples from 61 patients, we demonstrate widespread changes following infection. We identified gene expression signatures of severity, with the majority of pathways differentiating mild from severe disease in B cells and monocytes. For example, gene expression of PLAC8, a receptor known to modulate SARS-CoV-2 entry to cells, was a marker of severity in CD14+ monocytes. Longitudinal profiling demonstrated distinct temporal molecular trajectories in severe versus mild disease, including type 1 and type 2 interferon signalling, MHC gene expression and, in B cells, a proliferative signature (KRAS and MYC). Evaluation of clonal T cell dynamics showed that the fastest expanding clones were significantly enriched in known SARS-CoV-2 specific sequences and shared across multiple patients. Our analyses revealed novel TCR clones likely reactive to SARS-CoV-2. Finally, we identified a population of transcriptionally distinct monocytes that emerged in peripheral blood following glucocorticoid treatment. Overall, our data delineate the temporal dynamics of the immune response in COVID-19 in a high-risk population and provide a valuable open-access resource.
One of the most common causes of death globally is oral squamous cell carcinomas (OSCC), which are brought on by several etiological factors, including alcoholism, tobacco use, poor oral hygiene, infection with the human papillomavirus (HPV), and candida infections. Dysbiosis of the oral microbiota and inflammatory conditions like periodontitis have been implicated as causative causes in recent times. The homeostasis of the oral tumor microenvironment (TME) may be further altered by interactions between the microbiota and the host. Aim & Objectives: We wanted to determine the role that the resident microbiota plays in oral cancer progression, as well as decipher how it interacts with the TME. The article also discusses potential biomarkers and therapeutic targets to enhance the management of oral cancer. Study Design: PubMed, Medline, and Google Scholar are biomedical literature databases. The following keywords were looked up for academic literature using Boolean operators. Initially, a total of 273 articles were found as a result of the literature search. Finall, 142 articles those met the exclusion and inclusion criteria were chosen for this review. Discussion: Multiple oral bacterial species are linked to OSCCs. Modulation immunotherapies that target the tumor microenvironment (TME) and reverse oral microbiota dysbiosis have been proposed in recent investigations. Changes in the oral microbiota have an impact on the oral microenvironment, leading to inflammatory cell infiltration, cytokine release, and chronic inflammation, all of which support an immunosuppressive TME. Antifungal and antibacterial medications are currently advised for treatment. In conclusion, the utilization of microbial biomarkers and their generated products as anticancer medicines is one of the potential therapy methods for oral cancer. Tumor immunotherapies are the newest method for treating cancer patients, however there are still a lot of drawbacks. Possible approaches to immunotherapy are outlined.
Macrophages are a highly plastic cell type that adopt distinct subtypes and functional states depending on environmental cues. These functional states can vary wildly, with distinct macrophages capable of displaying opposing functions. We sought to understand how macrophage subtypes that exist on two ends of a spectrum influence the function of other cells. We used a co-culture system with primary human macrophages to probe the effects of macrophage subtypes on breast cancer cell proliferation. Our studies revealed a surprising phenotype in which both macrophage subtypes inhibited cancer cell proliferation compared to cancer cells alone. Of particular interest, using two different proliferation assays with two different breast cancer cell lines, we showed that differentiating macrophages into a pro-tumor subtype inhibited breast cancer cell proliferation. These findings are inconsistent with the prevailing interpretation that pro-tumor macrophages promote cancer cell proliferation and suggest a re-evaluation of how these interpretations are made.
Background
There is a lack of effective imaging tools for the clinical confirmation of chronic osteomyelitisis. At present, there are few studies/reports on the diagnosis of chronic osteomyelitisis by nuclear medicine at home and abroad. In this study, we retrospectively observed the accuracy of 99mTC-MDP and 99mTC-SC bone scanning imaging for the diagnosis of chronic osteomyelitisis and explored the clinical value of the two nuclear medicine imaging modalities for the diagnosis of chronic osteomyelitisis.
Methods
Patients who underwent 99mTC-MDP or 99mTC-SC bone scan imaging with surgical treatment for suspected chronic osteomyelitisis in our hospital from January 2019 to December 2022 were retrospectively analyzed. They were categorized into the 99mTC-MDP group and 99mTC-SC group according to their bone scan imaging modality. The bone scan results were also compared with the postoperative pathology and culture results to clarify the accuracy of the two imaging modalities.
Results
A total of 72 patients were included, including 38 patients in the 99mTC-MDP group and 34 patients in the 99mTC-SC group. A total of 51 patients were diagnosed with chronic osteomyelitisis. Bone scanning imaging in the 99mTC-MDP group showed positive results in 29 cases and negative results in 9 cases, consistent with the final pathologic diagnosis in 24 cases and inconsistent with the final pathologic diagnosis in 14 cases. Bone scanning imaging in the 99mTC-SC group showed positive results in 27 cases and negative results in 7 cases, consistent with the final pathologic diagnosis in 29 cases and inconsistent with the final pathologic diagnosis in 5 cases. The sensitivity, specificity, misdiagnosis rate, leakage rate, positive predictive value, negative predictive value, and accuracy of 99mTC-MDP bone scan for the diagnosis of chronic osteomyelitisis were 80% (20/25), 30.77% (4/13), 69.23% (9/13), 20% (5/25), 68.97% (20/29), and 44.44% (4/9), respectively, 63.16% (24/38); the sensitivity, specificity, misdiagnosis rate, leakage rate, positive predictive value, negative predictive value, and accuracy of 99mTC-SC bone scan for diagnosing chronic osteomyelitisis were 92.31% (24/26), 62.5% (5/8), 37.5% (3/8), 7.69% (2/26), and 88.89% (24/27), respectively, 71.43% (5/7), 85.29% (29/34). The accuracy of the two tests by chi-square test (2) was 2 = 8.25, P < 0.05, so 99mTC-SC bone scanning imaging was more accurate than 99mTC-MDP bone scanning imaging in diagnosing chronic osteomyelitisis.
Conclusion
Based on the current results, 99mTC-SC has a higher diagnostic accuracy for chronic osteomyelitisis than 99mTC-MDP bone scan imaging.
Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.
Recent evidence suggests that tumor-associated myeloid cells (TAMCs), which include tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC), play a significant role in cancer immunosuppression and progression. These cells constitute up to 50% of a tumor's total mass and play pivotal roles in dampening the immune response, thereby negatively affecting patient survival. Therefore, targeting TAMCs could overcome the limitations of current cancer treatments. Yet, drug development in this realm remains limited. Our research focuses on leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), prominently expressed on the surface of TAMs, which is essential in mediating the immunosuppressive role of TAMs. We have uncovered a previously unrecognized immunosuppressive LAIR1→ Factor XIII A (FXIII-A)→ Collagen IV circuit across cancer types. The LAIR1 triggers TAMs to release the FXIII-A around tumor cells, which increases tumor collagen IV deposition and structure, shielding the tumors from immune attacks. Inhibiting LAIR1, either through genetic knock-out (LAIR1-/-) or antibody blockade (aLAIR1), effectively disrupts this immunosuppressive pathway and results in enhanced peripheral and tumor-infiltrating memory CD8 T cell populations, a phenotypic shift of TAMs towards an M1 profile, and a decrease in collagen deposition. These collective effects contribute to the normalization of the TME and facilitate improved interactions between T cells and tumor cells, leading to a more effective antitumor response. Notably, using aLAIR1 as a standalone intervention or combined with Chimeric antigen receptor (CAR) T cell therapy demonstrates enhanced antitumor efficacy in preclinical models resistant to anti-PD-1 treatment. These findings position aLAIR1 as a promising strategy for cancer immunotherapy.
Macrophages are prime therapeutic targets due to their pro-tumorigenic and immunosuppressive functions in tumors, but varying efficacy of therapeutic approaches targeting macrophages highlights our incomplete understanding of how the tumor microenvironment (TME) can influence regulation of macrophages. The circadian clock is a key internal regulator of macrophage function, but how circadian rhythms of macrophages may be influenced by the tumor microenvironment remains unknown. We found that conditions associated with the TME such as polarizing stimuli, acidic pH, and elevated lactate concentrations can each alter circadian rhythms in macrophages. Circadian rhythms were enhanced in pro-resolution macrophages but suppressed in pro-inflammatory macrophages, while acidic pH had divergent effects on circadian rhythms depending on macrophage phenotype. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate that pH-driven changes in circadian rhythms are not mediated solely by the cAMP signaling pathway. Remarkably, clock correlation distance analysis of tumor-associated macrophages (TAMs) revealed evidence of circadian disorder in TAMs. This is the first report providing evidence that circadian rhythms of macrophages are altered within the TME. Our data suggest that heterogeneity in circadian rhythms at the population level may underlie this circadian disorder. Finally, we sought to determine how circadian regulation of macrophages impacts tumorigenesis, and found that tumor growth was suppressed when macrophages had a functional circadian clock. Our work demonstrates a novel mechanism by which the tumor microenvironment can influence macrophage biology through altering circadian rhythms, and the contribution of circadian rhythms in macrophages to suppressing tumor growth.
Background: Emerging investigations have increasingly highlighted the critical role of tumor-associated macrophages (TAMs) and M2 macrophages in cancer development, progression, and metastasis, marking them as potential targets in various cancer types. The main objective of this research is to discover new biomarkers associated with TAM-M2 in colorectal cancer (CRC) by combining single-cell RNA sequencing and bulk RNA-seq data. Our objective is to dissect the molecular heterogeneity of CRC and develop a novel risk signature.
Methods: By utilizing weighted gene co-expression network analysis (WGCNA), we acquired TAM-M2-associated genes by intersecting TAM marker genes obtained from scRNA-seq data with module genes of M2 macrophages derived from bulk RNA-seq data. We employed least absolute shrinkage and selection operator (LASSO) Cox analysis to select predictive biomarkers from these TAM-M2-related genes. Quantitative Polymerase Chain Reaction (qPCR) was employed to validate the mRNA expression levels of the genes identified in the screening. This led to the development of the TAM-M2-related signature (TAMM2RS). We also conducted immune landscape analysis across different risk groups.
Results: The combination of scRNA-seq and bulk RNA-seq analyses yielded 377 TAM-M2-related genes. DAPK1, NAGK, and TRAF1 emerged as key prognostic genes in CRC, identified through LASSO Cox analysis. Utilizing these genes, we constructed and validated the TAMM2RS, demonstrating its effectiveness in predicting survival in CRC patients.
Conclusion: Our research offers a thorough investigation into the molecular mechanisms associated with TAM-M2 macrophages in CRC and unveils potential therapeutic targets, offering new insights for treatment strategies in colorectal cancer.
Glaucoma is a neurodegenerative disease of the retina characterized by the irreversible loss of retinal ganglion cells (RGCs) leading to visual loss. Degeneration of RGCs and loss of their axons, as well as damage and remodeling of the lamina cribrosa are the main events in the pathogenesis of glaucoma. Different molecular pathways are involved in RGC death, which are triggered and exacerbated as a consequence of a number of risk factors such as elevated intraocular pressure (IOP), age, ocular biomechanics, or low ocular perfusion pressure. Increased IOP is one of the most important risk factors associated with this pathology and the only one for which treatment is currently available, nevertheless, on many cases the progression of the disease continues, despite IOP control. Thus, the IOP elevation is not the only trigger of glaucomatous damage, showing the evidence that other factors can induce RGCs death in this pathology, would be involved in the advance of glaucomatous neurodegeneration. The underlying mechanisms driving the neurodegenerative process in glaucoma include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress and neuroinflammation. In glaucoma, like as other neurodegenerative disorders, the immune system is involved and immunoregulation is conducted mainly by glial cells, microglia, astrocytes, and Müller cells. The increase in IOP produces the activation of glial cells in the retinal tissue. Chronic activation of glial cells in glaucoma may provoke a proinflammatory state at the retinal level inducing blood retinal barrier disruption and RGCs death. The modulation of the immune response in glaucoma as well as the activation of glial cells constitute an interesting new approach in the treatment of glaucoma.
Although primary and memory responses against bacteria and viruses have been studied extensively, T helper type 2 (T(H)2) effector mechanisms leading to host protection against helminthic parasites remain elusive. Examination of the intestinal epithelial submucosa of mice after primary and secondary infections by a natural gastrointestinal parasite revealed a distinct immune-cell infiltrate after challenge, featuring interleukin-4-expressing memory CD4(+) T cells that induced IL-4 receptor(hi) (IL-4R(hi)) CD206(+) alternatively activated macrophages. In turn, these alternatively activated macrophages (AAMacs) functioned as important effector cells of the protective memory response contributing to parasite elimination, demonstrating a previously unknown mechanism for host protection against intestinal helminths.
The nuclear factor kappaB (NF-kappaB) signaling pathway is important in cancer-related inflammation and malignant progression. Here, we describe a new role for NF-kappaB in cancer in maintaining the immunosuppressive phenotype of tumor-associated macrophages (TAMs). We show that macrophages are polarized via interleukin (IL)-1R and MyD88 to an immunosuppressive "alternative" phenotype that requires IkappaB kinase beta-mediated NF-kappaB activation. When NF-kappaB signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a "classically" activated phenotype; IL-12(high), major histocompatibility complex II(high), but IL-10(low) and arginase-1(low). Targeting NF-kappaB signaling in TAMs also promotes regression of advanced tumors in vivo by induction of macrophage tumoricidal activity and activation of antitumor activity through IL-12-dependent NK cell recruitment. We provide a rationale for manipulating the phenotype of the abundant macrophage population already located within the tumor microenvironment; the potential to "re-educate" the tumor-promoting macrophage population may prove an effective and novel therapeutic approach for cancer that complements existing therapies.
Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.
There has been substantial research activity in the past decade directed at phenotyping macrophage lineages and defining macrophage functional subsets or patterns of activity. The emphasis over the past 2-3 years has been to divide macrophage functional patterns into type 1 (Th1-driven) or type 2 (Th2-driven) functions. However, a huge array of environmental factors (including cytokines, chemokines, pattern recognition receptors, hormones) differentially regulates macrophage response patterns, resulting in the display of numerous distinct, functional phenotypes. Upon stimulation, a macrophage does not display just a single set of functions but rather displays a progression of functional changes in response to the progressive changes in its microenvironment. The remarkable ability of monocytes and tissue macrophages to adapt to changes in their microenvironment challenges the thesis that macrophages displaying unique tissue-specific or response-specific, functional patterns represent distinct lineages. With the exception of mature osteoclasts and mature dendritic cells, evidence supporting stable differentiation as the basis for macrophage functional heterogeneity is equivocal. The concept of whether macrophages develop into functional subsets as opposed to continuously adapting their functional pattern in response to the changing environment of a progressive inflammatory response is important to resolve from the perspectives of therapeutic targeting and understanding the role of macrophages in disease pathogenesis.
IL-17A was cloned more than 10 years ago and six IL-17 family members (IL-17A-F) have subsequently been described. IL-17A is largely produced by activated memory T lymphocytes but stimulates innate immunity and host defense. IL-17A and IL-17F both mobilize neutrophils partly through granulopoeisis and CXC chemokine induction, as well as increased survival locally. IL-17A and IL-17F production by T lymphocytes is regulated by IL-23 independent of T cell receptor activation. Increasing evidence shows that IL-17 family members play an active role in inflammatory diseases, autoimmune diseases, and cancer. This places IL-17 family members and their receptors as potential targets for future pharmacotherapy.
Macrophages are cells that function as a first line of defence against invading microorganisms. One of the hallmarks of macrophages is their ability to become activated in response to exogenous 'danger signals'. Most microbes have molecular patterns (PAMPS) that are recognized by macrophages and trigger this activation response. There are many aspects of the activation response to PAMPS that are recapitulated when macrophages encounter endogenous danger signals. In response to damaged or stressed self, macrophages undergo physiological changes that include the initiation of signal transduction cascades from germline-encoded receptors, resulting in the elaboration of chemokines, cytokines and toxic mediators. This response to endogenous mediators can enhance inflammation, and thereby contribute to autoimmune pathologies. Often the overall inflammatory response is the result of cooperative activation signals from both exogenous and endogenous signals. Macrophage activation plays a critical role, not only in the initiation of the inflammatory response but also in the resolution of this response. The clearance of granulocytes and the elaboration of anti-inflammatory mediators by macrophages contribute to the dissolution of the inflammatory response. Thus, macrophages are a key player in the initiation, propagation and resolution of inflammation. This review summarizes our understanding of the role of macrophages in inflammation. We pay particular attention to the endogenous danger signals that macrophages may encounter and the responses that these signals induce. The molecular mechanisms responsible for these responses and the diseases that result from inappropriately controlled macrophage activation are also examined.
Enteric nematode infection induces a strong type 2 T helper cell (Th2) cytokine response characterized by increased infiltration of various immune cells, including macrophages. The role of these immune cells in host defense against nematode infection remains poorly defined. The present study investigated the role of macrophages and the arginase pathway in nematode-induced changes in intestinal smooth muscle function and worm expulsion.
Mice were infected with Nippostrongylus brasiliensis and treated with clodronate-containing liposome to deplete macrophages or given S-(2-boronoethyl)-I-cysteine in drinking water to inhibit arginase activity. Segments of intestinal smooth muscle were suspended in organ baths to determine responses to acetylcholine, 5-hydroxytryptamine, or nerve stimulation. The phenotype of macrophages was monitored by measuring mRNA expression of the specific molecular markers by real-time polymerase chain reaction or viewed by immunofluorescence staining.
Infection increased the infiltration of macrophages and up-regulation alternatively activated macrophage markers by a mechanism dependent on interleukin-4 (IL-4) or interleukin-13 (IL-13) activation of signal transducer and activator of transcription 6. Elimination of alternatively activated macrophages blocked smooth muscle hypercontractility and the increased smooth muscle thickness, and impaired worm expulsion. In addition, specific inhibition of arginase activity interfered with smooth muscle contractility, but only partially affected the protective immunity of the host.
These data show that the phenotype of macrophages is determined by the local immune environment and that alternatively activated macrophages play a major role in the effects of Th2 cytokines, IL-4 and IL-13, on intestinal smooth muscle function.
This report presents themes highlighted during the eclectic and stimulating Metchnikoff's Legacy in 2008 meeting hosted at the Institut Pasteur in April 2008 in honor of the 100th anniversary of the 1908 Nobel Prize.