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Fibrosis is the extensive deposition of fibrous connective tissue, and it is characterized by the accumulation of collagen and other extracellular matrix (ECM) components. Fibrosis is essential for wound healing and tissue repair in response to a variety of triggers, which include infection, inflammation, autoimmune disorder, degenerative disease,...
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The immune system is a tightly regulated network which allows the development of defense mechanisms against foreign antigens and tolerance toward self-antigens. Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses. Dysregulation of any of these proce...
Citations
... On the other hand, TGF-b secreted by T cells provides Th17 differentiation and triggers IL-17 production. Increased TGF-b in the medium increases the expression of the Th17 cell transcription factor RORct and causes an increase in IL-17 (40). Increased TGF-b and increased IL-17 in our study support the literature finding. ...
The study aimed to investigate the expression profiles of transcription factors, cytokines, and co‐stimulatory molecules in helper T (Th)‐cell subsets within bronchoalveolar lavage (BAL) samples of patients with interstitial lung diseases (ILDs). Twenty ILDs patients were included in the study, comprising those with idiopathic pulmonary fibrosis (IPF) (n:8), autoimmune‐related ILDs (auto‐ILD) (n:4), and orphan diseases (O‐ILD) (n:8), alongside five control subjects. Flow cytometry was employed to evaluate the Th to cytotoxic T cell (CTL) ratio in BAL fluid, while cytopathological examination assessed macrophages, lymphocytes, and neutrophils. Quantitative real‐time polymerase chain reaction was utilized to investigate the expressions in Th1, Th2, Th17, and regulatory T (Treg) cells. Results revealed elevated Th cell to CTL ratios across all patient groups compared to controls. Furthermore, upregulation of Th1, Th2, Th17, and T‐cell factors was observed in all patient groups compared to controls. Interestingly, upregulation of CD28 and downregulation of CTLA‐4 and PD‐1 gene expression were consistent across all ILDs groups, highlighting potential immune dysregulation. This study provides a comprehensive exploration of molecular immunological mechanisms in ILDs patients, underscoring the dominance of Th2 and Th17 responses and revealing novel findings regarding the dysregulation of CD28 , CTLA‐4 , and PD‐1 expressions in ILDs for the first time.
... Numerous studies have demonstrated that immunological mediators released from immune cells lead to fibrosis and fibrotic disorders. 52,[65][66][67] Therefore, these results prompted us to investigate immune response and immune-infiltrated subtypes in the lacrimal glands. ...
... Moreover, in the postacute period of coronavirus infection in a part of patients, we can also see persisting damage in the myocardium, which can potentially lay the foundation for the formation of autoinflammatory diseases and promote progressive collagen deposition in the interstitium [38]. Also, impaired T-cell function has been observed in the background of coronavirus infection, thus potentially leading to overstimulation of myocardial myofibroblasts and contributing to the development of a profibrotic state [39][40][41][42][43]. Given that we are still only collecting data on the cardiovascular effects of SARS-CoV-2, additional time is required to fully evaluate the progression of cardiovascular disease on the COVID-19 background and to clarify the role of infection in the development of myocardial fibrosis [43]. ...
... Also, impaired T-cell function has been observed in the background of coronavirus infection, thus potentially leading to overstimulation of myocardial myofibroblasts and contributing to the development of a profibrotic state [39][40][41][42][43]. Given that we are still only collecting data on the cardiovascular effects of SARS-CoV-2, additional time is required to fully evaluate the progression of cardiovascular disease on the COVID-19 background and to clarify the role of infection in the development of myocardial fibrosis [43]. ...
Myocardial fibrosis is an important factor in the progression of cardiovascular diseases. However, there is still no universal lifetime method of myocardial fibrosis assessment that has a high prognostic significance. The aim of the study was to determine the significance of ventricular endomyocardial biopsies for the assessment of myocardial fibrosis and to identify the severity of myocardial fibrosis in different cardiovascular diseases. Material and Methods: Endomyocardial biopsies (EMBs) of 20 patients with chronic lymphocytic myocarditis (CM), endomyocardial fragments obtained during septal reduction of 21 patients with hypertrophic cardiomyopathy (HCM), and 36 patients with a long history of hypertensive and ischemic heart disease (HHD + IHD) were included in the study. The control group was formed from EMBs taken on 12–14 days after heart transplantation (n = 28). Also, for one patient without clinical and morphological data for cardiovascular pathology, postmortem myocardial fragments were taken from typical EMB and septal reduction sites. The relative area of fibrosis was calculated as the ratio of the total area of collagen fibers to the area of the whole biopsy. Endocardium and subendocardial fibrosis were not included in the total biopsy area. Results: The relative fibrosis area in the EMBs in the CM patient group was 5.6 [3.3; 12.6]%, 11.1 [6.6; 15.9]% in the HHD + IHD patient group, 13.4 [8.8; 16.7]% in the HCM patient group, and 2.7 [1.5; 4.6]% in the control group. When comparing the fibrosis area of the CM patients in repeat EMBs, it was found that the fibrosis area in the first EMBs was 7.6 [4.8; 12.0]%, and in repeat EMBs, it was 5.3 [3.2; 7.6]%. No statistically significant differences were found between the primary and repeat EMBs (p = 0.15). In ROC analysis, the area of fibrosis in the myocardium of 1.1% (or lower than one) was found to be highly specific for the control group of patients compared to the study patients. Conclusions: EMB in the assessment of myocardial fibrosis has a questionable role because of the heterogeneity of fibrotic changes in the myocardium.
... Th17 cells and Treg cells, as critical effector T cells in adaptive immunity, promote inflammation during cardiac tissue remodeling and lead to the pathogenesis of cardiac fibrosis (30,31). Moreover, it has been previously reported that LRG1 favors immune cell participation in systemic inflammation, which enhances the differentiation of naïve CD4 + T cells into pro-inflammatory Th17 lymphocytes by elevating interleukin 6 receptor; however, LRG1 has no influence on Treg differentiation (13). ...
Objective
Leucine-rich α-2 glycoprotein 1 (LRG1) promotes inflammation and myocardial injury, but its clinical role in ST-elevation myocardial infarction (STEMI) is rarely disclosed. Herein, this prospective study aimed to explore the value of plasma LRG1 at different time points to predict major adverse cardiovascular event (MACE) risk in patients with STEMI.
Methods
In total, 209 patients with STEMI were enrolled for determining plasma LRG1 at admission and on day (D)1/D7/D30 after admission via enzyme-linked immunosorbent assay, as well as for determination of peripheral blood T helper 17 (Th17) cells and regulatory T (Treg) cells by flow cytometry. In addition, plasma LRG1 was obtained from 30 healthy controls at enrollment.
Results
LRG1 was increased in patients with STEMI at admission compared with healthy controls (P < 0.001). In patients with STEMI, LRG1 varied at different time points (P < 0.001), which elevated from admission to D1, and gradually declined thereafter. LRG1 at admission was positively associated with Th17 cells (P = 0.001) and Th17/Treg ratio (P = 0.014). LRG1 at admission (P = 0.013), D1 (P = 0.034), D7 (P = 0.001), and D30 (P = 0.010) were increased in patients with MACE compared with those without. LRG1 at D7 exhibited good ability to estimate MACE risk (area under curve = 0.750, 95% confidence interval = 0.641–0.858). LRG1 at admission > 60 μg/ml (P = 0.031) and D7 > 60 μg/ml (P = 0.018) were linked with increased accumulating MACE. Importantly, LRG1 at D7 > 60 μg/ml was independently correlated with increased MACE risk (hazard ratio = 5.216, P = 0.033).
Conclusion
Plasma LRG1 increases from admission to D1 and gradually declines until D30, which positively links with Th17 cells and MACE risk in patients with STEMI.
... This can impose a significant burden on both patients and their families. Recent studies examining bronchial lavage fluid have suggested a close association between T cells and the development and progression of IPF [9]. This finding highlights the potential role of the immune system, particularly innate and adaptive immune processes, in coordinating fibrotic responses and influencing patient prognosis. ...
... T cells are pivotal in the fibrotic processes in various organs. For instance, they contribute to wound healing and tissue repair following liver injury, while exhibiting a protective role in kidney fibrosis [9,26]. Recently, several studies have highlighted the role of T cells in IPF. ...
... Additionally, Th17 cells can inhibit the immunosuppressive activity of CD4+FoxP3-expressing Tregs, favoring the progression of on-going lung inflammation and fibrosis [4]. Chronic inflammatory response in the lungs results in the continuous antigen-dependent priming of T cell receptors, resulting in the phosphorylation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR) in resting Tregs [44,45]. The activation of Akt/mTOR pathways alters the immunoregulatory phenotype of Tregs and induces their reprogramming into a pro-inflammatory Th17-like phenotype [45]. ...
Mesenchymal stem cell-derived exosomes (MSC-Exos) are nano-sized extracellular vesicles which contain various MSC-sourced anti-fibrotic, immunoregulatory and angio-modulatory proteins (growth factors, immunoregulatory cytokines, chemokines), lipids, and nucleic acids (messenger RNA and microRNAs). Due to their lipid envelope, MSC-Exos easily by-pass all barriers in the body and deliver their cargo directly in target cells, modulating their viability, proliferation, phenotype and function. The results obtained in recently published experimental studies demonstrated beneficial effects of MSC-Exos in the treatment of lung fibrosis. MSC-Exos reduced activation of fibroblasts and prevented their differentiation in myofibroblasts. By delivering MSC-sourced immunoregulatory factors in lung-infiltrated monocytes and T cells, MSC-Exos modulate their function, alleviating on-going inflammation and fibrosis. MSC-Exos may also serve as vehicles for the target delivery of anti-fibrotic and immunomodulatory agents, enabling enhanced attenuation of lung fibrosis. Although numerous pre-clinical studies have demonstrated the therapeutic potential of MSC-Exos in the treatment of pulmonary fibrosis, there are several challenges that currently hinder their clinical implementation. Therefore, in this review article, we summarized current knowledge and we discussed future perspectives regarding molecular and cellular mechanisms which were responsible for the anti-fibrotic, anti-inflammatory and immunoregulatory properties of MSC-Exos, paving the way for their clinical use in the treatment of lung fibrosis.
... ALGS is mainly caused by mutations in the Notch ligand JAGGED1 (JAG1, 94%) (Mašek & Andersson, 2017;Oda et al, 1997), resulting in bile duct paucity and cholestasis, but immune dysregulation has also been described (Tilib Shamoun et al, 2015). Cholestasisinduced inflammation results in fibrosis and cirrhosis driven by T cells (Zhang & Zhang, 2020;Shivakumar et al, 2007), natural killer (NK) cells (Shivakumar et al, 2009), and myeloid cells (Jin et al, 2019;Henderson et al, 2020), attracted to the liver by injured liver parenchyma (Allen et al, 2011). Conversely, fibrosis is attenuated by regulatory T cells (Zhang & Zhang, 2020). ...
... Cholestasisinduced inflammation results in fibrosis and cirrhosis driven by T cells (Zhang & Zhang, 2020;Shivakumar et al, 2007), natural killer (NK) cells (Shivakumar et al, 2009), and myeloid cells (Jin et al, 2019;Henderson et al, 2020), attracted to the liver by injured liver parenchyma (Allen et al, 2011). Conversely, fibrosis is attenuated by regulatory T cells (Zhang & Zhang, 2020). While Notch regulates T cell lineage specification in liver and thymus (Radtke et al, 2004;Herman et al, 2005;Chen et al, 2019), the function of Jag1 in this process is less clear. ...
... Tregs are anti-fibrotic in the context of the cholestatic liver injury (Roh et al, 2014;Zhang & Zhang, 2020), and were enriched in Jag1 Ndr/Ndr mice (Fig. 4), which could attenuate the CD4 + and CD8 + response to intestinal insult (Fig. 5). W therefore next tested Jag1 Ndr/Ndr T -cell effects on liver fibrosis. ...
Fibrosis is a physiological tissue repair mechanism, but excessive fibrosis can disrupt organ function. Alagille syndrome (ALGS), which is caused by mutations in the Notch ligand JAGGED1, results in bile duct paucity, neonatal cholestasis, and a characteristic fibrotic response. Here, we show that Jag1 Ndr/Ndr mice, a model for ALGS, recapitulates ALGS-like pericellular fibrosis. Single-cell RNA-seq and multi-color flow cytometry characterization of the liver and spleen revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration in cholestatic Jag1 Ndr/Ndr mice, despite an enrichment in extrahepatic (thymic and splenic) regulatory T cells (Tregs). Jag1 Ndr/Ndr lymphocyte immune and fibrot-ic capacity was tested with adoptive immune cell transplantation into Rag1-/-mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1 Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1 +/+ lymphocytes, in response to DSS. Cholestasis induced by BDL in Rag1-/-mice with Jag1 Ndr/Ndr lym-phocytes resulted in periportal Treg accumulation and threefold less periportal fibrosis than in Rag1-/-mice with Jag1 +/+ lymphocytes. Finally, we show that the Jag1 Ndr/Ndr hepatocyte expression profile and Treg overrepresentation are corroborated by transcriptomic data from children with ALGS. In sum, these data lead to a model in which Jag1-driven developmental hepatic and immune defects interact to determine the fibrotic process in ALGS.
... Arginase 1 converts arginine into precursors of proline essential for collagen production (4, 50). As well, macrophages upregulate proteases in response to T h 1 derived cytokines such as IFNg (53). IFNg may also impair collagen synthesis by fibroblasts and reduce pro-fibrotic IL-17 expression (1,44). ...
Tissue damage elicits a wound healing response of inflammation and remodeling aimed at restoring homeostasis. Dysregulation of wound healing leads to accumulation of effector cells and extracellular matrix (ECM) components, collectively termed fibrosis, which impairs organ functions. Fibrosis of the central nervous system, neurofibrosis, is a major contributor to the lack of neural regeneration and it involves fibroblasts, microglia/macrophages and astrocytes, and their deposited ECM. Neurofibrosis occurs commonly across neurological conditions. This review describes processes of wound healing and fibrosis in tissues in general, and in multiple sclerosis in particular, and considers approaches to ameliorate neurofibrosis to enhance neural recovery.
... T cells become activated in response to recognition of foreign antigens via a T cell antigen receptor-mediated signaling cascade that activates NF-κB-, AP-1-and NFAT-mediated transcriptional programs to promote cytokine release and proliferation [13][14][15][16] . Dysregulated T cell activation underlies graft-versus-host disease (GvHD), transplant rejection and various autoimmune conditions, and blocking aberrant T cell activation with cyclosporine represents a validated therapeutic axis [17][18][19] . However, on-target toxicities for cyclosporine and related agents have limited their applicability and have suggested the need for new targets regulating T cell activation. ...
... SP100030 has demonstrated efficacy in animal models of inflammatory disease, including rheumatoid arthritis, pulmonary fibrosis and transplant rejection 21,22,24 . We first sought to validate the previously reported efficacy of SP100030 in the bleomycin-induced model of idiopathic pulmonary fibrosis, in which T cells are known to contribute to disease progression 18,22 . Using established therapeutic doses of 10 and 30 mg per kg (body weight), mice treated with SP100030 for 7 days demonstrated dose-dependent suppression of a panel of cytokines associated with disease progression (Extended Data Fig. 9a). ...
Exportin-1 (XPO1/CRM1) plays a central role in the nuclear-to-cytoplasmic transport of hundreds of proteins and contributes to other cellular processes, such as centrosome duplication. Small molecules targeting XPO1 induce cytotoxicity, and selinexor was approved by the Food and Drug Administration in 2019 as a cancer chemotherapy for relapsed multiple myeloma. Here, we describe a cell-type-dependent chromatin-binding function for XPO1 that is essential for the chromatin occupancy of NFAT transcription factors and thus the appropriate activation of T cells. Additionally, we establish a class of XPO1-targeting small molecules capable of disrupting the chromatin binding of XPO1 without perturbing nuclear export or inducing cytotoxicity. This work defines a broad transcription regulatory role for XPO1 that is essential for T cell activation as well as a new class of XPO1 modulators to enable therapeutic targeting of XPO1 beyond oncology including in T cell-driven autoimmune disorders.
... Tregs may slow down the process of cardiac fibrosis by inhibiting the release of pro-fibrotic factors, which is crucial for the recovery of cardiac muscle function and structure (148,149). Additionally, Treg cells support post-MI recovery by regulating the differentiation of monocytes and macrophages into reparative M2 macrophages, diminishing post-infarction inflammation, restraining excessive matrix degradation, and thus slowing adverse morphological changes (64, 150).Accumulating Treg cells in the injured murine heart participate in regulating fibroblast behavior and function, inhibiting post-MI fibrosis, and alleviating cardiac stiffening and dysfunction (151). One study showed that Ccl17 deficiency leads to reduced left ventricular remodeling post-MI and after angiotensin II and norepinephrine administration. ...
In the genesis and progression of cardiovascular diseases involving both innate and adaptive immune responses, inflammation plays a pivotal and dual role. Studies in experimental animals indicate that certain immune responses are protective, while others exacerbate the disease. T-helper (Th) 1 cell immune responses are recognized as key drivers of inflammatory progression in cardiovascular diseases. Consequently, the CD4+CD25+FOXP3+ regulatory T cells (Tregs) are gaining increasing attention for their roles in inflammation and immune regulation. Given the critical role of Tregs in maintaining immune-inflammatory balance and homeostasis, abnormalities in their generation or function might lead to aberrant immune responses, thereby initiating pathological changes. Numerous preclinical studies and clinical trials have unveiled the central role of Tregs in cardiovascular diseases, such as atherosclerosis. Here, we review the roles and mechanisms of Treg subsets in cardiovascular conditions like atherosclerosis, hypertension, myocardial infarction and remodeling, myocarditis, dilated cardiomyopathy, and heart failure. While the precise molecular mechanisms of Tregs in cardiac protection remain elusive, therapeutic strategies targeting Tregs present a promising new direction for the prevention and treatment of cardiovascular diseases.
