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Macrophages play important roles in the clearance of dying and dead cells. Typically, and perhaps simplistically, they are viewed as the professional phagocytes of apoptotic cells. Clearance by macrophages of cells undergoing apoptosis is a non-phlogistic phenomenon which is often associated with actively anti-inflammatory phagocyte responses. By c...
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... of 'knock-out' mice has begun to help answer this question. As detailed in Table 2, several lines of mice pos- sessing engineered defects in individual genes implicated in apoptotic-cell clearance have been reported including C1q, ABCA1, SR-A, Mer, PSR, MFG-E8 and CD14 53,105-110 (Devitt, Gregory et al., submitted). In the context of redundancy of molecules mediating apoptotic-cell clear- ance, it would be surprising if absence or non-functionality of individual molecules were to produce phenotypic defects. ...
Citations
... The multifarious functions of macrophages extend beyond immunity, with research underscoring their fundamental role in maintaining the integrity of normal tissues. By rapidly identifying and removing apoptotic cells, macrophages ensure the preservation of typical tissue structure [8,56]. ...
Inner ear macrophages, also known as cochlear macrophages, are immune cells that play a crucial role in maintaining the homeostasis and hearing function of the inner ear. They are responsible for responses to cochlear insults, such as noise exposure, ototoxic drugs, and surgical injuries. These cells have been shown to be present in the spiral ganglion, spiral ligament, and stria vascularis of the inner ear. As our understanding of inner ear macrophages continues to evolve, it is becoming evident that these cells are not just inert populations in the auditory system but are active participants in the complicated mechanics of inner ear homeostasis. Nevertheless, a comprehensive understanding of the roles and functions of macrophages within the auditory system is lacking. This review explores the presence, origin, and multifaceted roles of inner ear macrophages, elucidating their significance in maintaining auditory function, while also highlighting their potential inimical role in inner ear inflammation. The information collated herein has important implications for the development of therapeutic strategies aimed at preserving or restoring auditory function.
... In the later stages of the illness, macrophages frequently act as a professional phagocyte in the thyroid follicular tissue to eliminate apoptotic cells. 36 In the current investigation, macrophages were seen in some thyroid follicles but not all of them. The heterogeneity in the lineage of the apoptotic cells responsible for macrophage activation might be the cause of this disparity. ...
Bluetongue virus (BTV), a major peril to the sheep industry, infects a wide range of the cells in the infected animals including mononuclear, dendritic and epithelial cells. However, little is known about its tropism for the secretory epithelial cells of endocrine glands and the pathogenesis it induces. The aim of the study was to assess the BTV load, antigen distribution in the tissue of the pituitary, thyroid as well as adrenal glands and associated histo-pathological consequences. BTV antigens were localized using immunohistochemistry in the thyroid's epithelial cells, zona fasciculata and zona reticularis cells and the anterior pituitary epithelial cells. The real-time PCR portrayed the high viral load in adrenals at 7 th days post-inoculation (DPI) and in thyroid and pituitary glands at 15 th DPI. Serum examination revealed variation in the T-3 and T-4 of infected animals in comparison to the control group. Caspase-3 immunolocalization revealed BTV-1 induces apoptosis in the affected cells of endocrine gland of infected animals. Further, this study signifies the tropism of BTV in the novel sites (endocrine glands) of the host that might be one of the reasons for the poor performance of infected animals.
... In the later stages of the illness, macrophages frequently act as a professional phagocyte in the thyroid follicular tissue to eliminate apoptotic cells. 36 In the current investigation, macrophages were seen in some thyroid follicles but not all of them. The heterogeneity in the lineage of the apoptotic cells responsible for macrophage activation might be the cause of this disparity. ...
Bluetongue virus (BTV), a major peril to the sheep industry, infects a wide range of the cells in the infected animals including mononuclear, dendritic and epithelial cells. However, little is known about its tropism for the secretory epithelial cells of endocrine glands and the pathogenesis it induces. The aim of the study was to assess the BTV load, antigen distribution in the tissue of the pituitary, thyroid as well as adrenal glands and associated histopathological consequences. BTV antigens were localized using immunohistochemistry in the thyroid's epithelial cells, zona fasciculata and zona reticularis cells and the anterior pituitary epithelial cells. The real-time PCR portrayed the high viral load in adrenals at 7th days postinoculation (DPI) and in thyroid and pituitary glands at 15th DPI. Serum examination revealed variation in the T-3 and T-4 of infected animals in comparison to the control group. Caspase-3 immunolocalization revealed BTV-1 induces apoptosis in the affected cells of endocrine gland of infected animals. Further, this study signifies the tropism of BTV in the novel sites (endocrine glands) of the host that might be one of the reasons for the poor performance of infected animals.
... This indicated that the DNA was cleaved by EESG. Unlike cell death (necrosis), apoptosis is a process in which cells die by themselves through a suicide signaling mechanism that occurs within cells 19) . Apoptosis is a process in which cells die on their own by suicide signaling mechanisms that rarely induce an immune response, and the cell remnants are removed by immune cells such as macrophages 19) . ...
... Unlike cell death (necrosis), apoptosis is a process in which cells die by themselves through a suicide signaling mechanism that occurs within cells 19) . Apoptosis is a process in which cells die on their own by suicide signaling mechanisms that rarely induce an immune response, and the cell remnants are removed by immune cells such as macrophages 19) . Apoptosis is induced by the activation of intracellular proteolytic enzymes called caspases 20) . ...
... It is certainly the case that small cells such as thymocytes often show no fragmentation as they undergo apoptosis.130 Macrophages, dendritic cells and a vast array of so-called non-professional phagocytes-which act as effective efferocytes of their apoptotic neighbors include epithelial and endothelial cells, fibroblasts, hepatocytes, satellite, mesangial, Sertoli and Paneth cells as well as various tumor cell types-are capable of engulfing apoptotic cells25,[152][153][154][155] ; some efferocytes can engulf whole corpses 156 even when only minimal morphological apoptotic features are apparent.157 It seems reasonable to expect, however, that ApoBD production-disassembly of the dying cell into "bite-sized" pieces that can be readily engulfed-could be especially important for improving the efficiency of uptake and degradation by the nonspecialized (i.e., non-macrophage) efferocytes that so frequently engulf their apoptotic neighbors. ...
Cancers are genetically driven, rogue tissues which generate dysfunctional, obdurate organs by hijacking normal, homeostatic programs. Apoptosis is an evolutionarily conserved regulated cell death program and a profoundly important homeostatic mechanism that is common (alongside tumor cell proliferation) in actively growing cancers, as well as in tumors responding to cytotoxic anti‐cancer therapies. Although well known for its cell‐autonomous tumor‐suppressive qualities, apoptosis harbors pro‐oncogenic properties which are deployed through non‐cell‐autonomous mechanisms and which generally remain poorly defined. Here, the roles of apoptosis in tumor biology are reviewed, with particular focus on the secreted and fragmentation products of apoptotic tumor cells and their effects on tumor‐associated macrophages, key supportive cells in the aberrant homeostasis of the tumor microenvironment. Historical aspects of cell loss in tumor growth kinetics are considered and the impact (and potential impact) on tumor growth of apoptotic‐cell clearance (efferocytosis) as well as released soluble and extracellular vesicle‐associated factors are discussed from the perspectives of inflammation, tissue repair, and regeneration programs. An “apoptosis‐centric” view is proposed in which dying tumor cells provide an important platform for intricate intercellular communication networks in growing cancers. The perspective has implications for future research and for improving cancer diagnosis and therapy.
... As we have seen, the cargoes of ApoEVs are at least as diverse as those of healthy cell-derived EVs. Classical characteristics of apoptosis are (a) frequently, fragmentation of dying cells into ApoBDs and (b) engulfment of apoptotic cells and bodiesoften referred to as efferocytosis or 'corpse clearance'by neighbouring healthy cells of multiple lineages acting opportunistically as efferocytes or by 'professional' mononuclear phagocytes, most commonly tissue macrophages [89,90]. In developmental and tissue homeostatic contexts, efficient efferocytosis provides a safe intracellular haven for the potentially pro-inflammatory and tissuedamaging effects of apoptotic-cell constituents, such as proteolytic enzymes and DNA, thereby militating against autoimmune and inflammatory pathologies. ...
Extracellular vesicles (EVs) are lipid bilayer-enclosed subcellular bodies produced by most, if not all cells. Research over the last two decades has recognised the importance of EVs in intercellular communication and horizontal transfer of biological material. EVs range in diameter from tens of nanometres up to several micrometres and are able to transfer a spectrum of biologically active cargoes - from whole organelles, through macromolecules including nucleic acids and proteins, to metabolites and small molecules - from their cells of origin to recipient cells, which may consequently become physiologically or pathologically altered. Based on their modes of biogenesis, the most renowned EV classes are (1) microvesicles, (2) exosomes (both produced by healthy cells), and (3) EVs from cells undergoing regulated death by apoptosis (ApoEVs). Microvesicles bud directly from the plasma membrane, while exosomes are derived from endosomal compartments. Current knowledge of the formation and functional properties of ApoEVs lags behind that of microvesicles and exosomes, but burgeoning evidence indicates that ApoEVs carry manifold cargoes, including mitochondria, ribosomes, DNA, RNAs, and proteins, and perform diverse functions in health and disease. Here we review this evidence, which demonstrates substantial diversity in the luminal and surface membrane cargoes of ApoEVs, permitted by their very broad size range (from around 50 nm to >5 μm; the larger often termed apoptotic bodies), strongly suggests their origins through both microvesicle- and exosome-like biogenesis pathways, and indicates routes through which they interact with recipient cells. We discuss the capacity of ApoEVs to recycle cargoes and modulate inflammatory, immunological, and cell fate programmes in normal physiology and in pathological scenarios such as cancer and atherosclerosis. Finally, we provide a perspective on clinical applications of ApoEVs in diagnostics and therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
... Independently of ROS generation, all anticancer therapies result in cell death. As discussed above, when cells die they are engulfed by specialized phagocytes, the macrophages, through the exposure of several molecules on their surface which are recognized by macrophage receptors [reviewed in Gregory and Devitt 2004]. Importantly, macrophages do not simply engulf and digest apoptotic cells, they respond to these cells by changing the profile of pro-and anti-inflammatory mediators that they release. ...
The inflammatory process often modifies the natural history of cancers. There is broad evidence that chronic inflammatory responses, associated with, e.g., persistent viral or bacterial infections, promote carcinogenesis. Cancer treatment is also associated with an inflammatory process that may either induce an antitumor immune response or, conversely, favor tumor recurrence. Here, we will revise the major aspects of therapy-induced inflammation and its consequences for tumor recurrence or repopulation, emphasizing how the mode of tumor cell death elicits an antitumor response, the key elements associated with the clearance of dead cells within the tumor microenvironment and the unleashing of an innate tissue regenerative response, dependent on lipid mediators such as prostaglandin E2 and the platelet activation factor (PAF), that favor tumor regrowth. Therapy-induced inflammation may offer a window of opportunity for combination therapies that increase the effectiveness of conventional cancer treatment modalities. Nanobiotechnology offers versatile platforms for anti-inflammatory interventions. Here we also discuss RNA-based approaches in the nanoscale, which would allow targeted interventions of pro-tumoral inflammatory milieu assembled in the course of therapeutic regimens in order to avoid the emergence of treatment-resistant cancer cells that ultimately repopulate the tumor mass.KeywordsInflammationCancer treatmentChemotherapyRadiotherapyImmunotherapyTumor repopulation
... Independently of ROS generation, all anticancer therapies result in cell death. As discussed above, when cells die they are engulfed by specialized phagocytes, the macrophages, through the exposure of several molecules on their surface which are recognized by macrophage receptors [reviewed in Gregory and Devitt 2004]. Importantly, macrophages do not simply engulf and digest apoptotic cells, they respond to these cells by changing the profile of pro-and anti-inflammatory mediators that they release. ...
Although heart diseases continue to be the leading cause of death worldwide, advances performed in recent decades have facilitated a decrease in the mortality rate related to severe heart diseases. This is due to the recognition that has been acquiring the role of the immune system and its contribution to the progression of heart disease. Recent studies have shown that there is a close relationship between cardiac disturbances and inflammatory mediators produced by immune system cells since there is a close interaction between the innate and adaptive immune response in the pathophysiology of heart diseases. Regarding innate immune response, macrophages are the leading cells, which play a fundamental role in a wide variety of cardiac disorders. These cells produce a variety of cytokines that open up a wide range of therapeutic possibilities in the treatment of heart diseases. However, under certain circumstances, it is known that immune system cells can cause irreparable damage that contributes to heart failure. Therefore, it is essential to study the crosstalk between innate and adaptive response in order to better understand the mechanism of action of the different cardiac disturbances. In this sense, biotechnology emerges as a pioneering tool that allows on the one hand to effectively detect the various cardiovascular and inflammatory diseases, and on the other, to develop innovative therapies that result in effective treatments.
... Macrophages are commonly known as the professional phagocytes of apoptotic cells (AC), as they spend most of their time phagocyting apoptotic cells and fragments, with >10 9 ACs generated in humans per day [3,11]. The maintenance of tissue homeostasis by efficient clearance of AC by macrophages is crucial to inhibit inflammatory and autoimmune responses against "self" antigens. ...
The Tyro, Axl, and MerTK receptors (TAMRs) play a significant role in the clearance of apoptotic cells. In this work, the spotlight was set on MerTK, as it is one of the prominent TAMRs expressed on the surface of macrophages and dendritic cells. MerTK-specific antibodies were previously isolated from a transgenic rat-derived immune library with suitable biophysical properties. Further characterisation resulted in an agonistic MerTK antibody that led to phospho AKT activation in a dose-dependent manner. In this proof-of-concept study, a MerTK-specific antibody, MerK28, was combined with tandem, biparatopic EGFR-binding VHH camelid antibody domains (7D9G) in different architectures to generate bispecific antibodies with the capacity to bind EGFR and MerTK simultaneously. The bispecific molecules exhibited appropriate binding properties with regard to both targets in their soluble forms as well as to cells, which resulted in the engagement of macrophage-like THP-1 cells with epidermoid carcinoma A431 cells. Furthermore, targeted phagocytosis in co-culture experiments was observed only with the bispecific variants and not the parental MerTK-binding antibody. This work paves the way for the generation of bispecific macrophage-engaging antibodies for targeted phagocytosis harnessing the immune-modulating roles of MerTK in immunotherapy.
... This marvel is due to the electrostatic revulsion between particles with the same electric charge, which triggers nanoparticle dispersion [37]. Upon being injected into the body of patients, nanocarriers intermingle with physiological fluids and are thereby recognized without difficulty by the immune system; consequently, phagocytes from the circulation system discard them [38]. Therefore, the interfacial potentials of MIO and MIO@RHAS15 were found to be − 26.62 and − 41.85 mV, respectively ( Fig. 5(a)). ...
In recent years, nanoscience has attracted considerable attention in the field of biomedicine. This involves the use of engineered nanomaterials as vital platforms for targeted drug delivery, diagnosis, imaging, and observation of therapeutic efficiency. This study explored the preparation, characterization, and applications of doxorubicin-loaded magnetic rice husk ash-derived SBA-15 (MIO@RHAS15-DOX nanocomposites) for drug delivery and in vitro/in vivo efficiency in the treatment of liver cancer. The small-angle XRD patterns of the MIO@RHAS15 nanocomposites demonstrated a core diffraction peak at 0.94°, with two noticeable peaks at 1.6° and 1.8°, representing (100), (110), and (200) crystalline planes, respectively, thereby indicating the existence of a well-defined mesostructure. A sharp melting endothermic peak (Tm) at 79 °C was observed for MIO@RHAS15 nanocomposites. The DOX release from MIO@RHAS15 followed the Higuchi model with the best correlation coefficient R2 value of 0.9799. The in vitro studies indicated a concentration dependent anticancer efficiency, with high cancer cells inhibition for MIO@RHAS15-DOX than free DOX. At the highest concentration of DOX (120 µg/mL), there was less than 25% and 15% cell viability after 24 h and 48 h, respectively. The in vivo studies demonstrated that the tumor sizes after treatment with PBS, MIO@RHAS15, free DOX, and MIO@RHS15-DOX were 1081, 904, 143, and 167 mm3, respectively. The in vivo animal test results depicted that the MIO@RHAS15-DOX nanocomposites were able to inhibit liver tumors in all tested mice. Therefore, the prepared nanocomposites possess a great potential for drug delivery application towards cancer treatment, thereby overcoming the limitations of traditional chemotherapy.
