Pathogenesis Of Systemic Sclerosis Research Articles

Genome-wide integrated DNA methylome and transcriptome analysis reveals a strong dysregulated myeloid component in the epigenetic landscape of Systemic Sclerosis.

Non-genetic factors influence Systemic Sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study (EWAS). We analyzed DNA methylation data from whole blood samples in 179 SSc patients and 241 unaffected individuals, to identify differentially methylated positions (DMPs) with a FDR<0.05. These results were further integrated with RNA-seq data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels. This analysis yielded 525 DMPs enriched in immune-related pathways, being leukocyte cell-cell adhesion the most significant (FDR=4.91x10-9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach we observed an enrichment of neutrophil related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein (CEBP) transcription factor family in SSc, which is crucial in the myeloid lineage development. Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.

Nerandomilast Improves Bleomycin-Induced Systemic Sclerosis-Associated Interstitial Lung Disease in Mice by Regulating the TGF-β1 Pathway.

Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common complication of SSc and a major contributor to SSc-related deaths. Besides nintedanib and tocilizumab, there are currently no clinically approved drugs for SSc-ILD, highlighting the urgent need for new treatment strategies. Previous studies have shown that cyclic adenosine monophosphate (cAMP) plays a crucial role in the pathogenesis of SSc and lung fibrosis. Phosphodiesterases (PDEs) are enzymes that specifically hydrolyze cAMP, making PDE inhibitors promising candidates for SSc-ILD treatment. Nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor currently undergoing phase III clinical trials for idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases (PF-ILD), has good preference for PDE4B but lacks studies for SSc-ILD. Our research demonstrates that nerandomilast effectively inhibits skin and lung fibrosis in a bleomycin-induced mouse model of SSc-ILD. For lung fibrosis, we found that nerandomilast could improve bleomycin-induced SSc-ILD through inhibiting PDE4B and the TGF-β1-Smads/non-Smads signaling pathways, which provides a theoretical basis for potential therapeutic drug development for SSc-ILD.

Molecular underpinnings of aging contributing to systemic sclerosis pathogenesis

Molecular underpinnings of aging contributing to systemic sclerosis pathogenesis

Inhibiting Triggering Receptor Expressed on Myeloid Cells-1 signaling to ameliorate skin fibrosis.

Systemic sclerosis (SSc) is characterized by immune system failure, vascular insult, autoimmunity, and tissue fibrosis. Transforming growth factor-beta (TGF-β) is a crucial mediator of persistent myofibroblast activation and aberrant extracellular matrix production in SSc. The factors responsible for this are unknown. By amplifying pattern recognition receptor signaling, Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) is implicated in multiple inflammatory conditions. In this study, we used novel ligand-independent TREM-1 inhibitors in order to investigate the pathogenic role of TREM-1 in SSc, using preclinical models of fibrosis, and explanted SSc skin fibroblasts. Selective pharmacological TREM-1 blockade prevented and reversed skin fibrosis induced by bleomycin in mice and mitigated constitutive collagen synthesis and myofibroblast features in SSc fibroblasts in vitro. Our results implicate aberrantly activated TREM-1 signaling in SSc pathogenesis, identify a unique approach to TREM-1 blockade, and suggest a potential therapeutic benefit for TREM-1 inhibition.

An overview of the role of chemokine CX3CL1 (Fractalkine) and CX3C chemokine receptor 1 in systemic sclerosis.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrosis, vascular damage, and immune dysregulation. Fractalkine or chemokine (C-X3-C motif) ligand 1 (CX3CL1), a chemokine and adhesion molecule, along with its receptor CX3CR1, have been implicated in the inflammatory processes of SSc. CX3CL1 functions as both a chemoattractant and an adhesion molecule, guiding immune cell trafficking. This systematic review examines the role of CX3CL1 and its receptor CX3CR1 in the pathogenesis of SSc, with a focus on pulmonary and vascular complications. A systematic literature search was conducted across databases including PubMed, Scopus, and Web of Science from inception to November 2020. The search focused on studies investigating the CX3CL1/CX3CR1 axis in the context of SSc. The review identified elevated CX3CL1 expression in SSc patients, particularly in the skin and lungs, where CX3CR1 is expressed on infiltrating immune cells. Higher levels of CX3CL1 were correlated with the severity of interstitial lung disease in SSc patients, indicating a potential predictive marker for disease progression. CX3CR1-positive monocytes and NK cells were recruited to inflamed tissues, contributing to fibrosis and tissue damage. Animal studies showed that inhibition of the CX3CL1/CX3CR1 axis reduced fibrosis and improved vascular function. The CX3CL1/CX3CR1 axis plays a key role in immune cell recruitment and fibrosis in SSc. Elevated CX3CL1 levels are associated with lung and vascular complications, making it a potential biomarker for disease progression and a promising therapeutic target.

Single-cell transcriptomes and chromatin accessibility of endothelial cells unravel transcription factors associated with dysregulated angiogenesis in systemic sclerosis

ObjectivesVasculopathy emerges early in systemic sclerosis (SSc) and links to endothelial cell (EC) injury and angiogenesis. Understanding EC transcriptomes and epigenomes is crucial for unravelling the mechanisms involved.MethodsTranscriptomes and chromatin...

Mycophenolate mofetil directly modulates myeloid viability and pro-fibrotic activation of human macrophages.

Mycophenolate mofetil (MMF) is an immunosuppressant used to treat rheumatological diseases, including Systemic Sclerosis (SSc). While MMF is an established inhibitor of lymphocyte proliferation, recent evidence suggests MMF also mediates effects on other cell types. The goal of this study was to determine the effect of MMF on monocytes and macrophages, which have been implicated in SSc pathogenesis. Human monocyte-derived macrophages were cultured with the active MMF metabolite, mycophenolic acid (MPA), and assessed for changes in viability and immuno-phenotype. Guanosine supplementation studies were performed to determine whether MPA-mediated effects were dependent on de novo purine synthesis. The ability of MPA-treated macrophages to induce fibroblast activation was evaluated, and dermal myeloid expression signatures were analyzed in MMF-treated SSc patients. MPA reduced viability and induced apoptosis in monocytes and macrophages at doses (average IC50 = 1.15 µg/ml) within the target serum concentration of MMF patients (1-3µg/ml). These effects were reversed by guanosine supplementation. Low-dose MPA (0.5 µg/ml) attenuated IL-4 or SSc plasma-mediated macrophage activation, and inhibited the ability of SSc plasma-activated macrophages to induce SSc fibroblast activation. Gene expression studies demonstrated significant reductions in dermal myeloid signatures in MMF-responsive SSc patients. For the first time, we demonstrate that MMF inhibits the viability and pro-fibrotic activation of human monocytes and macrophages, which is dependent on de novo purine synthesis. Coupled with myeloid gene expression attenuation following MMF treatment in patients, these results suggest that fibrotic inhibition observed with MMF may be attributable, at least in part, to direct effects on myeloid cells.

Unraveling the role of MiR-181 in skin fibrosis pathogenesis by targeting NUDT21.

Systemic sclerosis (SSc) is a life-threatening autoimmune disease characterized by widespread fibrosis in the skin and several internal organs. Nudix Hydrolase 21 (NUDT2 or CFIm25) downregulation in fibroblasts is known to play detrimental roles in both skin and lung fibrosis. This study aims to investigate the upstream mechanisms that lead to NUDT21 repression in skin fibrosis. We identified transforming growth factor β (TGFβ1) as the primary cytokine that downregulated NUDT21 in normal skin fibroblasts. In the bleomycin-induced dermal fibrosis model, consistent with the peak activation of TGFβ1 at the late fibrotic stage, NUDT21 was downregulated at this stage, and delayed NUDT21 knockdown during this fibrotic phase led to enhanced fibrotic response to bleomycin. Further investigation suggested TGFβ downregulated NUDT21 through microRNA (miRNA) 181a and 181b induction. Both miR-181a and miR-181b were elevated in bleomycin-induced skin fibrosis in mice and primary fibroblasts isolated from SSc patients, and they directly targeted NUDT21 and led to its downregulation in skin fibroblasts. Functional studies demonstrated that miR-181a and miR-181b inhibitors attenuated bleomycin-induced skin fibrosis in mice in association with decreased NUDT21 expression, while miR-181a and miR-181b mimics promoted bleomycin-induced fibrosis. Overall, these findings suggest a novel role for miR-181a/b in SSc pathogenesis by repressing NUDT21 expression.

Pathogenic role of anti-nuclear autoantibodies in systemic sclerosis: Insights from other rheumatic diseases.

Systemic sclerosis (SSc) is a severe autoimmune disease characterized by vasculopathy, fibrosis, and dysregulated immunity, with hallmark autoantibodies targeting nuclear antigens such as centromere protein (ACA) and topoisomerase I (ATA). These autoantibodies are highly prevalent and disease-specific, rarely coexisting, thus serving as crucial biomarkers for SSc diagnosis. Despite their diagnostic value, their roles in SSc pathogenesis remain unclear. This review summarizes current literature on ACA and ATA in SSc, comparing them to autoantibodies in other rheumatic diseases to elucidate their potential pathogenic roles. Similarities are drawn with anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis, particularly regarding disease specificity and minimal pathogenic impact of antigen binding. In addition, differences between ANA and ACPA in therapeutic responses and Fab glycosylation patterns are reviewed. While ACA and ATA are valuable for disease stratification and monitoring activity, understanding their origins and the associated B cell responses is critical for advancing therapeutic strategies for SSc.

Disturbed Complement Receptor Expression Pattern of B Cells Is Enhanced by Toll-like Receptor CD180 Ligation in Diffuse Cutaneous Systemic Sclerosis.

Autoantibody production is a hallmark of systemic sclerosis (SSc) and the most extensively studied role of B cells in the pathogenesis of the disease. However, the potential involvement of innate immune molecules in B-cell dysfunction in SSc is less understood. B-cell activation is an early event in the pathogenesis of SSc and is influenced by complement receptors (CRs) and Toll-like receptors (TLRs), shaping antibody responses. CR2 and CR1 modulate B-cell activation, and the roles of CR3 and CR4 are associated with autoimmune conditions. We investigated the expression of CRs in B cells from patients with the more severe form of the disease, diffuse cutaneous SSc (dcSSc), and the effect of TLR CD180 ligation on their expression. We found no significant difference in the basal expression of CD21 and CD11c in B cells between dcSSc and healthy controls (HCs). However, reduced basal CD11b expression in B cells in dcSSc compared to HCs, accompanied by a decrease in CD35 and an increase in CD11c expression following CD180 ligation may promote plasma cell formation and autoantibody production. Additionally, we searched for correlations between dcSSc-associated anti-DNA topoisomerase I (Scl-70) autoantibody, anti-citrate synthase (CS) natural autoantibody and complement component 3 (C3) levels and found a negative correlation between C3 and anti-CS autoantibody in dcSSc but not in HCs, supporting the hypothesis that natural autoantibodies could activate the complement system contributing to tissue injury in SSc.

Understanding the gastrointestinal microbiome in systemic sclerosis: methodological advancements and emerging research.

This review highlights the role of the gastrointestinal (GI) microbiome in systemic sclerosis (SSc). We describe techniques for evaluating the GI microbiome in humans, and emerging research linking GI microbiome alterations (i.e., dysbiosis) and distinct SSc clinical manifestations. We also address the evolving treatment landscape targeting dysbiosis in SSc. Recent literature brings into focus the complex relationship between the GI microbiome and SSc pathogenesis. Advanced techniques (e.g., shotgun metagenomics, meta-transcriptomics) provide deeper insights into microbial taxonomy and active gene expression, exposing dysbiosis as a potential driver of SSc. New studies demonstrate that SSc patients who possess specific SSc clinical features, (e.g., interstitial lung disease), have unique GI microbiome profiles. Dysbiosis is associated with specific clinical features in patients with SSc. New tools for studying the GI microbiome have furthered our understanding of the relationship between dysbiosis and SSc complications. Therapeutic avenues such as dietary adjustments, probiotics, antibiotics, mindfulness practices, and fecal transplants offer potential for managing SSc and preventing its progression through GI microbiome modulation. By clarifying what is known about the relationship between the GI dysbiosis, GI dysfunction, and SSc, this review enhances our understanding of SSc pathogenesis and proposes targeted interventions.

The Phenotypes and Functions of Neutrophils in Systemic Sclerosis.

Systemic sclerosis (SSc) is a chronic disease of the connective tissue characterized by its multifaceted impact on various bodily systems, yet its precise cause remains elusive. Central to its pathology are abnormal immune activation, vasculopathy, and consequent fibrosis affecting both the skin and internal organs. The intricate interplay between the innate and adaptive immune systems significantly influences the pathogenesis of SSc. Despite substantial research, the role of neutrophils, key players in innate immunity, in the context of SSc has remained enigmatic. Emerging evidence suggests that neutrophils not only contribute to the initiation and perpetuation of SSc but also inflict damage on organs and promote fibrosis-a hallmark of the disease in many patients. This review aims to investigate the nuanced involvement of neutrophils in the development of SSc. By shedding light on the intricate mechanisms through which neutrophils influence the pathogenesis of SSc, we can gain deeper insights into the disease process and potentially identify novel therapeutic targets. Understanding the precise role of neutrophils may pave the way for more targeted and effective interventions to alleviate the burden of SSc on affected individuals.

Talabostat, fibroblast activation protein inhibitor, attenuates inflammation and fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive fibrosis, where activated fibroblasts play a pivotal role in disease progression. This study aimed to investigate the potential of Talabostat, a small molecule inhibitor of dipeptidyl peptidases, in alleviating fibrosis and inflammation associated with SSc pathogenesis. Dermal fibroblasts were obtained from skin biopsies of ten diffuse cutaneous SSc patients and healthy controls. These fibroblasts were subjected to treatment with either TGF-β alone or in combination with Talabostat. Immunofluorescence staining was conducted to evaluate FAPα and α-SMA protein levels. The expression of activated fibroblast markers (FAPα and ACAT2), pro-fibrotic (COL1A1 and COL1A2), anti-fibrotic (MMP1, MMP2, and MMP9), and inflammatory (IL-6 and TGFβ1) related genes was measured by quantitative real-time PCR. Talabostat-treated fibroblasts were assessed for their migratory capacity using a scratch assay and for their viability through MTT assay and Annexin V staining. The basal expression of COL1A1 and TGFβ1 was notably higher in healthy subjects, while MMP1 expression showed a significant increase in SSc patients. Furthermore, TGF-β stimulation led to upregulation of activated fibroblast markers, pro-fibrotic, and inflammatory-related genes in SSc-derived fibroblasts, which were attenuated upon Talabostat treatment. Interestingly, Talabostat treatment resulted in an upregulation of MMP9 expression. Moreover, Talabostat exhibited a concentration-dependent inhibition of activated fibroblast viability in both healthy and SSc fibroblasts, and suppressed fibroblast migration specifically in SSc patients. In summary, Talabostat modulates fibrotic genes in SSc, thereby inhibiting myofibroblast differentiation, activation, and migration. These findings suggest promising therapeutic avenues for targeting fibrosis in SSc.

Toll-Like Receptor 8 is Expressed in Monocytes in Contrast to Plasmacytoid Dendritic Cells and Mediates Aberrant Interleukin-10 Responses in Patients With Systemic Sclerosis.

Systemic sclerosis (SSc) is a severe rheumatic disease causing fibrotic tissue rearrangement. Aberrant toll-like receptor (TLR) 8 transcripts in plasmacytoid dendritic cells (pDCs) were recently linked to SSc pathogenesis, which is at least partially mediated by increased type I interferon (IFN-I) responses. Here, we addressed the functional role of TLR8 signaling in different immune cell subsets of patients with SSc. Monocytes, conventional dendritic cells (cDCs), and pDCs from the blood and skin of patients with SSc were analyzed for TLR8 protein expression. To assess TLR function, cytokine responses upon TLR7 and TLR8 stimulation were studied. To identify relevant alterations specific for patients with SSc (n = 16), patients with primary Sjögren disease (pSS; n = 10) and healthy controls (HCs; n = 13) were included into the study. In all individuals, TLR8 was expressed in monocytes and cDCs but not in pDCs. The TLR8 expression levels were overall similar in patients with SSc and pSS and HCs. Additionally, in all study participants, TLR8 stimulation of pDCs did not induce IFN-I expression. In contrast, monocytes from patients with SSc revealed increased interleukin (IL)-10 responses upon TLR8 (patients with SSc vs HCs, P = 0.0126) and TLR7/8 stimulation (patients with SSc vs HCs, P = 0.0170). TLR8 protein is not expressed in pDCs of patients with SSc. Accordingly, they do not respond to TLR8 stimulation. In contrast, monocytes of patients with SSc respond to TLR8 stimulation with increased IL-10 responses. Therefore, TLR8 signaling in monocytes participates in SSc pathogenesis by conferring aberrant IL-10 expression.

Update on systemic sclerosis

The updates to the European recommendations and the German guidelines for the treatment of systemic sclerosis are expected shortly, which are very good evidence-based guidelines for all those treating the disease; however, there are still disease manifestations with insufficient studies and current study results that were published after the review of the literature for the guidelines and might be of interest to the reader. The aim of this work is to provide an overview of the publications in the last year that are interesting from the authors' point of view. The aim is to provide practically relevant information on the current state of knowledge that can supplement the guidelines. The pathogenesis of systemic sclerosis (SSc) is becoming better understood in its interplay between environmental factors and the development of autoantibodies. There have also been overviews of the manifestation and prognosis of cardiac involvement in the last year. The American Thoracic Society issued the first guidelines for the treatment of interstitial lung disease in SSc. There are an increasing number of studies that suggest that disease-modulating combination therapies, such as rituximab and mycophenolate mofetil (MMF) are beneficial. Work addressing the involvement of joints suggests that inflammatory changes are common. Current options for the treatment of gastrointestinal involvement are presented. The diagnosis and treatment of systemic sclerosis is making progress and many symptoms and complications are treatable. Nevertheless, much remains to be done to improve the quality of life of the patients.

A randomised, parallel-group, double-blind, placebo-controlled phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis: DAISY study design and rationale.

The type I interferon pathway is a promising target for treatment of patients with systemic sclerosis (SSc). Here, we describe the design of a multinational, randomised phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis (DAISY). DAISY includes a 52-week double-blind, placebo-controlled treatment period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. The patient population includes a planned 306 adults with limited or diffuse cutaneous active SSc who satisfied American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria. Use of standard immunosuppressants, including mycophenolate mofetil, at a stable dose prior to randomisation is permitted in addition to weekly subcutaneous anifrolumab or placebo. Efficacy will be assessed at Week 52 via Revised-Composite Response Index in SSc (CRISS)-25 response (primary endpoint). Lung function and skin thickness will be assessed via change from baseline in forced vital capacity in patients with SSc-associated interstitial lung disease and modified Rodnan Skin Score, respectively (key secondary endpoints). The DAISY trial will evaluate the efficacy and safety of anifrolumab as a first-in-class treatment option for patients with both limited and diffuse cutaneous SSc and will provide insight into the contributions of type I interferon to SSc pathogenesis. Revised-CRISS-25 can account for improvement and worsening in a broad set of validated clinical measures beyond lung function and skin thickness, including clinician- and patient-reported outcomes, capturing the heterogeneity of SSc.

Systemic sclerosis: one year in review 2024.

Systemic sclerosis (SSc) is a rare and chronic connective tissue disease of unknown aetiology and characterised by three main pathogenetic events represented by endothelial damage, inflammation with activation of the immune system leading to production of specific autoantibodies and finally fibrosis. SSc is a heterogeneous disease and the classification in two subsets, the limited cutaneous (lcSSc) subset and the diffuse cutaneous one (dcSSc), is not capable of capturing the broad and different phenotypic expression of the disease. In the last years progress has been made in the knowledge of SSc pathogenesis, in its early diagnosis and new therapeutic strategies have been proposed, however, the management of SSc still represents a challenge for the clinician. For this reason, every year several studies investigate new insights of disease pathogenesis, internal organ involvement and therapeutic approaches. The purpose of this review is to provide an overview of the literature published in 2023.

Autoantibodies as putative biomarkers and triggers of cell dysfunctions in systemic sclerosis.

Antinuclear autoantibodies represent a serological hallmark of systemic sclerosis (SSc), with anticentromere, antitopoisomerase-I, and anti-RNA polymerase III antibodies routinely assessed for diagnosis, clinical subset classification, and prognosis. In addition, an increasing number of autoantibodies have been demonstrated to play a pathogenic role by mediating different SSc manifestations. This review aims to give an overview on autoantibodies as putative biomarkers in SSc and discuss their possible pathogenic role as triggers of cell dysfunctions. Over the years, different autoantibodies have been proposed as biomarkers aiding in diagnosis, disease subtype classification, disease progression prediction, organ involvement, as well as in understanding treatment response. Increasing literature also indicates functional autoantibodies as direct contributors to SSc pathogenesis by exerting agonistic or antagonistic activities on their specific cognate targets. In SSc, search and validation of novel autoantibodies with higher diagnostic specificity and more accurate predictive values are increasingly needed for early diagnosis and specific follow-up, and to define the best therapeutic option according to different disease subsets. Moreover, since autoantibodies are also emerging as functional pathogenic players, a better unraveling of their possible pathomechanisms becomes essential to identify new targets and develop promising therapeutic agents able to neutralize their effects.

The effect of gut microbiome and plasma metabolome on systemic sclerosis: a bidirectional two-sample Mendelian randomization study.

Cellular and molecular biology, combined with research on the human microbiome and metabolome, have provided new insights into the pathogenesis of systemic sclerosis (SSc). However, most studies on gut microbiota (GM) and metabolome in SSc are observational studies. The impact of confounding factors and reverse causation leads to different insights. To shed light on this matter, we utilized Mendelian randomization (MR) to determine the causal effect of GM/metabolites on SSc. Based on summary-level data from genome-wide association studies, bidirectional Two-sample MR was conducted involving 196 GM, 1400 plasma metabolism, and 9,095 SSc. Inverse Variance Weighting (IVW) was mainly used for effect estimation. Forward MR analysis found that three GM and two plasma metabolites are causally related to SSc. IVW results showed Victivallaceae (family) (OR, 1.469; 95%CI, 1.099-1.963; p = 0.009) and LachnospiraceaeUCG004 (genus) (OR, 1.548; 95%CI, 1.020-2.349; p = 0.04) were risk factor of SSc. Conversely, Prevotella7 (genus) (OR, 0.759; 95%CI, 0.578-0.997; p = 0.048)was a protective factor of SSc. The results on plasma metabolites indicated that Pregnenediol disulfate (C21H34O8S2) levels (OR, 1.164; 95%CI, 1.006-1.347; p = 0.041)was a risk factor of SSc, while Sphingomyelin (d18:1/19:0, d19:1/18:0) levels (OR, 0.821; 95%CI, 0.677-0.996; p = 0.045)was a protective factor of SSc. Reverse MR analysis did not find causally relationship between SSc and the above GM/plasma metabolites. Our results revealed the causally effect between GM/plasma metabolites and SSc. These findings provided new insights into the mechanism of SSc. In particular, we demonstrated Prevotella7 was a protective factor of SSc despite its controversial role in SSc in previous researches.

Could Gas6/TAM Axis Provide Valuable Insights into the Pathogenesis of Systemic Sclerosis?

Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular injury, extracellular matrix deposition, autoimmunity, inflammation, and fibrosis. The clinical complexity and high heterogeneity of the disease make the discovery of potential therapeutic targets difficult. However, the recent progress in the comprehension of its pathogenesis is encouraging. Growth Arrest-Specific 6 (Gas6) and Tyro3, Axl, and MerTK (TAM) receptors are involved in multiple biological processes, including modulation of the immune response, phagocytosis, apoptosis, fibrosis, inflammation, cancer development, and autoimmune disorders. In the present manuscript, we review the current evidence regarding SSc pathogenesis and the role of the Gas6/TAM system in several human diseases, suggesting its likely contribution in SSc and highlighting areas where further research is necessary to fully comprehend the role of TAM receptors in this condition. Indeed, understanding the involvement of TAM receptors in SSc, which is currently unknown, could provide valuable insights for novel potential therapeutic targets.