A potential contribution of antimicrobial peptide LL-37 to tissue fibrosis and vasculopathy in systemic sclerosis

2016 ◽  
Vol 175 (6) ◽  
pp. 1195-1203 ◽  
Author(s):  
T. Takahashi ◽  
Y. Asano ◽  
K. Nakamura ◽  
T. Yamashita ◽  
R. Saigusa ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Antimicrobial Peptide ◽  
Potential Contribution ◽  
Tissue Fibrosis

scholarly journals Contribution of Interleukin-6 to the Pathogenesis of Systemic Sclerosis

2017 ◽  
Vol 2 (2_suppl) ◽  
pp. S6-S12 ◽  
Author(s):  
Yasushi Kawaguchi
Keyword(s):  
Clinical Trials ◽  
Growth Factors ◽  
Systemic Sclerosis ◽  
Interleukin 6 ◽  
Systemic Circulation ◽  
Unknown Etiology ◽  
Tissue Fibrosis ◽  
Biological Features ◽  
The Past

Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology, manifesting in patients as tissue fibrosis, endothelial dysfunction, and inflammation. The disease is characterized by autoantibodies, a hallmark of autoimmunity. Various cytokines and growth factors are elevated in the systemic circulation and fibrotic lesions of patients with SSc. In particular, several studies over the past 2 decades have shown that interleukin-6 (IL-6) appears to be involved in the pathogenesis of SSc. Based on the association between aberrant IL-6 production and tissue fibrosis in patients with SSc, the anti-IL-6 receptor antibody, tocilizumab, is being investigated in clinical trials. This article reviews the biological features of IL-6 and the IL-6 receptor; the role of IL-6 in the pathogenesis of SSc; and the potential for IL-6 inhibition to be used in the treatment of patients with SSc.

A potential contribution of decreased galectin‐7 expression in stratified epithelia to the development of cutaneous and oesophageal manifestations in systemic sclerosis

2019 ◽  
Vol 28 (5) ◽  
pp. 536-542 ◽  
Author(s):  
Ryosuke Saigusa ◽  
Takashi Yamashita ◽  
Shunsuke Miura ◽  
Megumi Hirabayashi ◽  
Kouki Nakamura ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Potential Contribution ◽  
Stratified Epithelia

scholarly journals Pathogenic Roles of Autoantibodies and Aberrant Epigenetic Regulation of Immune and Connective Tissue Cells in the Tissue Fibrosis of Patients with Systemic Sclerosis

2020 ◽  
Vol 21 (9) ◽  
pp. 3069
Author(s):  
Chang-Youh Tsai ◽  
Song-Chou Hsieh ◽  
Tsai-Hung Wu ◽  
Ko-Jen Li ◽  
Chieh-Yu Shen ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Th2 Cells ◽  
Limited Data ◽  
Autoantibody Production ◽  
Tissue Fibrosis ◽  
Epigenetic Modifiers ◽  
Non Coding Rnas ◽  
Collagen Genes ◽  
Molecular Bases

Systemic sclerosis (SSc) is a multi-system autoimmune disease with tissue fibrosis prominent in the skin and lung. In this review, we briefly describe the autoimmune features (mainly autoantibody production and cytokine profiles) and the potential pathogenic contributors including genetic/epigenetic predisposition, and environmental factors. We look in detail at the cellular and molecular bases underlying tissue-fibrosis which include trans-differentiation of fibroblasts (FBs) to myofibroblasts (MFBs). We also state comprehensively the pro-inflammatory and pro-fibrotic cytokines relevant to MFB trans-differentiation, vasculopathy-associated autoantibodies, and fibrosis-regulating microRNAs in SSc. It is conceivable that tissue fibrosis is mainly mediated by an excessive production of TGF-β, the master regulator, from the skewed Th2 cells, macrophages, fibroblasts, myofibroblasts, and keratinocytes. After binding with TGF-β receptors on MFB, the downstream Wnt/β-catenin triggers canonical Smad 2/3 and non-canonical Smad 4 signaling pathways to transcribe collagen genes. Subsequently, excessive collagen fiber synthesis and accumulation as well as tissue fibrosis ensue. In the later part of this review, we discuss limited data relevant to the role of long non-coding RNAs (lncRNAs) in tissue-fibrosis in SSc. It is expected that these lncRNAs may become the useful biomarkers and therapeutic targets for SSc in the future. The prospective investigations in the development of novel epigenetic modifiers are also suggested.

Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis

2012 ◽  
Vol 64 (8) ◽  
pp. 2724-2733 ◽  
Author(s):  
Angelika Horn ◽  
Katrin Palumbo ◽  
Cinzia Cordazzo ◽  
Clara Dees ◽  
Alfiya Akhmetshina ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Hedgehog Signaling ◽  
Tissue Fibrosis ◽  
Fibroblast Activation

Fli1-deficient γδT cells augment tissue fibrosis and vasculopathy in a murine model of systemic sclerosis via increased IL-17A production

2017 ◽  
Vol 86 (2) ◽  
pp. e2
Author(s):  
Ryosuke Saigusa ◽  
Yoshihide Asano ◽  
Takuya Miyagawa ◽  
Megumi Hirabayashi ◽  
Kouki Nakamura ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Murine Model ◽  
Γδt Cells ◽  
Tissue Fibrosis

scholarly journals Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors

2004 ◽  
Vol 50 (1) ◽  
pp. 216-226 ◽  
Author(s):  
Yasushi Kawaguchi ◽  
Kae Takagi ◽  
Masako Hara ◽  
Chikako Fukasawa ◽  
Tomoko Sugiura ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Angiotensin Ii ◽  
Tissue Fibrosis ◽  
Lesional Skin

scholarly journals New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 610
Author(s):  
Eloisa Romano ◽  
Irene Rosa ◽  
Bianca Saveria Fioretto ◽  
Marco Matucci-Cerinic ◽  
Mirko Manetti
Keyword(s):  
Endothelial Cells ◽  
Systemic Sclerosis ◽  
Vessel Wall ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Vascular Wall ◽  
Vascular Lesions ◽  
Tissue Fibrosis ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

In systemic sclerosis (SSc), abnormalities in microvessel morphology occur early and evolve into a distinctive vasculopathy that relentlessly advances in parallel with the development of tissue fibrosis orchestrated by myofibroblasts in nearly all affected organs. Our knowledge of the cellular and molecular mechanisms underlying such a unique relationship between SSc-related vasculopathy and fibrosis has profoundly changed over the last few years. Indeed, increasing evidence has suggested that endothelial-to-mesenchymal transition (EndoMT), a process in which profibrotic myofibroblasts originate from endothelial cells, may take center stage in SSc pathogenesis. While in arterioles and small arteries EndoMT may lead to the accumulation of myofibroblasts within the vessel wall and development of fibroproliferative vascular lesions, in capillary vessels it may instead result in vascular destruction and formation of myofibroblasts that migrate into the perivascular space with consequent tissue fibrosis and microvessel rarefaction, which are hallmarks of SSc. Besides endothelial cells, other vascular wall-resident cells, such as pericytes and vascular smooth muscle cells, may acquire a myofibroblast-like synthetic phenotype contributing to both SSc-related vascular dysfunction and fibrosis. A deeper understanding of the mechanisms underlying the differentiation of myofibroblasts inside the vessel wall provides the rationale for novel targeted therapeutic strategies for the treatment of SSc.

scholarly journals SAT0287 AMPLIFICATION OF THE PRO-FIBROTIC JAK2-STAT3 SIGNALING AXIS BY TGFΒ-INDUCED EPIGENETIC SILENCING OF SOCS3

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1088.2-1088
Author(s):  
C. Dees ◽  
S. Poetter ◽  
Y. Zhang ◽  
C. Bergmann ◽  
X. Zhou ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Promoter Hypermethylation ◽  
Epigenetic Silencing ◽  
Research Support ◽  
Tissue Fibrosis ◽  
Fibroblast Activation ◽  
Stat3 Signaling ◽  
Stat Signaling ◽  
Fibrotic Diseases

Background:Tissue fibrosis caused by a pathological activation of fibroblasts is a major hallmark of systemic sclerosis (SSc). Epigenetic gene silencing of anti-fibrotic genes is thought to play a central role to establish the persistently activated phenotype of fibroblasts independent of external stimuli such as TGFβ, which has been identified as key-mediator of fibroblast activation.Objectives:The aims of the present study were to investigate whether the aberrant activation of JAK2-STAT3 signaling in fibrosis might be caused by epigenetic silencing of SOCS expression and whether re-establishment of the endogenous, SOCS-dependent control of JAK / STAT signaling may prevent aberrant fibroblast activation and ameliorate tissue fibrosis.Methods:The methylation status of SOCS3 in fibroblasts was evaluated by methylation-specific PCR and MeDIP assays. 5-aza-2-deoxycytidine (5-aza) and siRNA was used to inhibit DNA methyltransferases (DNMTs)in vitroandin vivo. Knockdown and overexpression experiments served to analyze the mechanism of action in cultured fibroblasts. Fibroblast-specific knockout mice were additionally used to analyze the role of SOCS3 and DNMTsin vivo.Results:Chronically increased levels of TGFβ reduced the expression of SOCS3 in normal fibroblasts to a level also found in SSc fibroblasts. Consistently, the expression of SOCS3 was severely downregulated in skin of SSc patients compared to healthy individuals with only minor differences between limited and diffuse cutaneous SSc. Methylation analyses demonstrated a prominent promoter hypermethylation of SOCS3 in SSc fibroblasts and in normal fibroblasts exposed to persistently high levels of TGFβ. Increased DNMT activity and a time-dependent induction of DNMT3A and DNMT1 expression upon chronic exposure to TGFβ resulted in promoter hypermethylation of SOCS3. Knockdown of SOCS3 induced an SSc-like phenotype in normal dermal fibroblasts with increased activation of JAK2-STAT3 signaling, enhanced expression of myofibroblast markers, increased collagen release, and aggravated experimental tissue fibrosis with increased activation of JAK2-STAT3 signaling. This effect was mimicked by overexpression of mutant JAK2 with mutations in the SOCS3 binding motif. Vice versa, forced overexpression of SOCS3 reduced TGFβ-mediated fibroblast activation and ameliorated the endogenous activation of SSc fibroblasts. Pharmacological inhibition or selective knockdown of DNMTs restored the normal expression of SOCS3, reduced fibroblast activation and collagen release, blocked STAT3-responsive transcription, and exerted potent antifibrotic effects in bleomycin- and TBRIact-induced dermal fibrosis. In addition, treatment with 5-aza or knockdown of either DNMT1 or DNMT3A induced regression of established fibrosis.Conclusion:These findings identify a novel pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of new targeted therapies in fibrotic diseases. We demonstrate that the chronic activation of TGFβ signaling in fibrotic diseases perturbs the epigenetic control of STAT signaling by DNMT-induced silencing of SOCS3 expression. Our data might thus strengthen the scientific rational for targeting DNA methylation in fibrotic diseases.Disclosure of Interests:Clara Dees: None declared, Sebastian Poetter: None declared, Yun Zhang: None declared, Christina Bergmann: None declared, xiang zhou: None declared, Markus Luber: None declared, Emmanuel Karouzakis: None declared, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim

scholarly journals Molecular Basis of Accelerated Aging with Immune Dysfunction-Mediated Inflammation (Inflamm-Aging) in Patients with Systemic Sclerosis

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3402
Author(s):  
Chieh-Yu Shen ◽  
Cheng-Hsun Lu ◽  
Cheng-Han Wu ◽  
Ko-Jen Li ◽  
Yu-Min Kuo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Systemic Sclerosis ◽  
Cellular Senescence ◽  
Cancer Incidence ◽  
Molecular Basis ◽  
Chromosome Instability ◽  
Vascular Endothelial Cell ◽  
Accelerated Aging ◽  
Immune Dysfunction ◽  
Tissue Fibrosis

Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by immune dysregulation, chronic inflammation, vascular endothelial cell dysfunction, and progressive tissue fibrosis of the skin and internal organs. Moreover, increased cancer incidence and accelerated aging are also found. The increased cancer incidence is believed to be a result of chromosome instability. Accelerated cellular senescence has been confirmed by the shortening of telomere length due to increased DNA breakage, abnormal DNA repair response, and telomerase deficiency mediated by enhanced oxidative/nitrative stresses. The immune dysfunctions of SSc patients are manifested by excessive production of proinflammatory cytokines IL-1, IL-6, IL-17, IFN-α, and TNF-α, which can elicit potent tissue inflammation followed by tissue fibrosis. Furthermore, a number of autoantibodies including anti-topoisomerase 1 (anti-TOPO-1), anti-centromere (ACA or anti-CENP-B), anti-RNA polymerase enzyme (anti-RNAP III), anti-ribonuclear proteins (anti-U1, U2, and U11/U12 RNP), anti-nucleolar antigens (anti-Th/T0, anti-NOR90, anti-Ku, anti-RuvBL1/2, and anti-PM/Scl), and anti-telomere-associated proteins were also found. Based on these data, inflamm-aging caused by immune dysfunction-mediated inflammation exists in patients with SSc. Hence, increased cellular senescence is elicited by the interactions among excessive oxidative stress, pro-inflammatory cytokines, and autoantibodies. In the present review, we will discuss in detail the molecular basis of chromosome instability, increased oxidative stress, and functional adaptation by deranged immunome, which are related to inflamm-aging in patients with SSc.

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