Abstract
Systemic sclerosis is a profibrotic autoimmune disease mediated by the dysregulation of extracellular matrix synthesis. Formyl peptide receptor 2 (Fpr2) is a G protein-coupled receptor that modulates inflammation and host defense by regulating the activation of inflammatory cells, such as macrophages. However, the role of Fpr2 in the development and therapy of scleroderma is still unclear. The present study was conducted to investigate the effects of Fpr2 activation in the treatment of scleroderma fibrosis. We found that intradermal administration of WKYMVm, an Fpr2-specific agonist, alleviated bleomycin-induced scleroderma fibrosis in mice and decreased dermal thickness in scleroderma skin. WKYMVm-treated scleroderma skin tissues displayed reduced numbers of myofibroblasts expressing α-smooth muscle actin, Vimentin, and phosphorylated SMAD3. WKYMVm treatment attenuated macrophage infiltration in scleroderma skin and reduced the number of M2 macrophages. The therapeutic effects of WKYMVm in scleroderma-associated fibrosis and inflammation were completely abrogated in Fpr2 knockout mice. Moreover, WKYMVm treatment reduced the serum levels of inflammatory cytokines, such as tumor necrosis factor-α, and interferon-γ, in the scleroderma model of wild-type mice but not in Fpr2 knockout mice. These results suggest that WKYMVm-induced activation of Fpr2 leads to alleviation of fibrosis by stimulating immune resolution in systemic sclerosis.
Highlights
Systemic sclerosis or scleroderma is a multiple autoimmune and inflammatory connective tissue disease, resulting in extensive tissue fibrosis in multiple organs
To explore whether Formyl peptide receptor 2 (Fpr2) activation directly regulates the differentiation of fibroblasts to α-smooth muscle actin (α-SMA)-positive myofibroblasts, we examined the effects of WKYMVm on myofibroblast differentiation induced by transforming growth factor-β1 (TGF-β1), which is a well-known ligand that induces myofibroblast differentiation [20]
We showed that WKYMVm-induced activation of Fpr2 reduced the skin fibrosis which is associated with
Summary
Systemic sclerosis or scleroderma is a multiple autoimmune and inflammatory connective tissue disease, resulting in extensive tissue fibrosis in multiple organs. Prominent skin and organ fibrosis is a hallmark feature of scleroderma and is accompanied by fibro-proliferative vasculopathy and immune dysfunction [1, 2]. Activated fibroblasts or myofibroblasts, characterized by increased expression of α-smooth muscle actin (α-SMA) and Vimentin, are the key effector cells in scleroderma. Differentiation of fibroblasts into myofibroblasts increases the production of extracellular matrix components, such as collagen, with subsequent development of fibrosis [1, 3]. Fibroblast recruitment and differentiation to myofibroblasts are regulated by a combination of autocrine and paracrine profibrotic mediators.
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