Abstract
BackgroundSystemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models.MethodsThe anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated.ResultsDZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor β1, connective tissue growth factor, tumor necrosis factor-α, interferon-γ, IL-1β, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-β1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-β/Smad signaling pathway.ConclusionsDZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis.
Highlights
Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis
DZ2002-treated group (DZ2002) alleviates skin fibrosis in BLM-induced Systemic sclerosis (SSc) mice model We evaluated the effect of DZ2002 on BLM-induced dermal fibrosis
We found that DZ2002 suppressed the mRNA expression of vascular endothelial growth factor (VEGF) in mice skin tissue (Fig. 1e)
Summary
Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. Systemic sclerosis (SSc), known as scleroderma, is a systemic autoimmune disease characterized by early inflammation and vascular injury followed by fibrosis of the skin and visceral organs [1,2,3]. M1 macrophages can promote tissue inflammation by producing pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, IL-6, and IL-12. M2 macrophages can induce or maintain tissue fibrosis by producing profibrotic cytokines, including TGF-β, IL-4, and IL-13. T helper (Th) 1 cells and their secreted interferon-γ (IFN-γ) are effective anti-fibrosis factors [12]. In SSc, Th2 cells promote the polarization of M2 by producing IL-4 and IL13, while M2 macrophages produce IL-13 to promote Th2 differentiation, creating a positive feedback loop [14]. Overall, regulating Th1/Th2/Th17 cell balance and inhibiting macrophage polarization are effective strategies for the treatment of SSc
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