Abstract
Systemic sclerosis (SSc) is a progressive fibrotic disease that affects the skin and internal organs. Despite evidence implicating increased interleukin-17 (IL-17) activity in SSc, the role of IL-17 in SSc remains uncertain. The purpose of this study was to investigate whether IL-17 plays a pathophysiological role in SSc in two different murine models of SSc. Bleomycin (BLM)-induced fibrosis and chronic graft-versus-host disease (cGVHD) models were used. Histological analysis was performed using Masson's trichrome and immunohistochemical staining. Quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunoassays were used to quantify the messenger RNA and protein levels of inflammatory mediators in dermal fibroblasts. IL-1 receptor antagonist-deficient (IL-1Ra-KO) mice were more severely affected by BLM injection, as shown by dermal and pulmonary fibrosis, compared with wild-type (WT) mice. Increased tissue fibrosis was reversed by knocking down IL-17. In vitro experiments showed that IL-1 and IL-17 exerted synergistic effects on the expression of profibrotic and inflammatory mediators. In the cGVHD model, C57BL/6 mice receiving splenocytes of IL-1Ra-KO BALB/c mice developed more severe cGVHD than did those receiving cells from WT mice. Knockdown of IL-17 in IL-1Ra-KO donor mice significantly attenuated the IL-1-induced acceleration of cGVHD severity. Targeting IL-1 and its downstream IL-17 activity may be a novel treatment strategy for inhibiting inflammation and tissue fibrosis in SSc.
Highlights
Systemic sclerosis (SSc) is a progressive fibrotic disease that is characterized by excessive deposition of extracellular matrix (ECM) components such as collagen and glycoprotein [1]
IL-1 receptor antagonist (IL-1Ra)-KO mice were backcrossed to IL-17 KO mice over 10 generations, and double KO (DKO) mice were selected for use in polymerase chain reaction (PCR) analysis
In addition to IL-6, matrix metalloproteinase (MMP), type 1 collagen, and excessive transforming growth factor β (TGF-β) activity are revealed to be closely associated with pathological fibrosis in SSc patients [23]
Summary
Systemic sclerosis (SSc) is a progressive fibrotic disease that is characterized by excessive deposition of extracellular matrix (ECM) components such as collagen and glycoprotein [1]. CD4+ T cells have recently been shown to be centrally involved in the pathogenesis of SSc. In addition to vasculopathy and fibrosis, activated autoimmunity is another hallmark of SSc. In the preclinical or very early phase, the pathological changes in skin affected by SSc include perivascular edema and inflammatory cell infiltration [4]. In lungs affected by SSc, inflammatory cell infiltration in the interstitium and alveoli precedes evident pulmonary fibrosis [5]. These observations strongly suggest that the infiltration of inflammatory cells such as CD4+ T cells is the first event in the process leading to the generalized tissue fibrosis in SSc
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
