Abstract
Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc.
Highlights
Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity
IL-31 overproduction in the sera of SSc patients correlated with fibrosis and Th2 up-regulation, the major features of the disease
In this study, we showed the efficacy of anti-IL-31 receptor A (IL-31RA) monoclonal antibody (mAb) in a murine model of SSc
Summary
Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Cytokines and chemokines that enhance Th2 immune responses play important roles in SSc. For instance, IL-6, which is overexpressed in SSc patients, contributes to the development of SSc by driving Th2 differentiation as well as promoting collagen production in fibroblasts[15,16,17,18]. IL-6, which is overexpressed in SSc patients, contributes to the development of SSc by driving Th2 differentiation as well as promoting collagen production in fibroblasts[15,16,17,18] Taken together, these studies suggest that Th2 dominance is a key immunological feature of SSc that directly and indirectly promotes fibrosis. Yaseen et al have shown that IL-31 and IL-31RA are up-regulated in patients with SSc34 They have demonstrated the pro-fibrotic effects of IL31 in human dermal fibroblasts (DFs) and SSc model mice. These backgrounds led us to further explore the roles of IL-31 in SSc and its potential as a therapeutic target
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