Abstract
Fibrosis is a pathological hallmark of systemic sclerosis, a deadly autoimmune disease affecting the connective tissues of multiple organs. However, the immune mechanisms underlying fibrosis and systemic sclerosis remain unclear. To determine the initiating immune pathway in fibrosis, we investigated the role of type 2 alarmin cytokines in the mouse model of skin fibrosis. Wild-type mice that received subcutaneous bleomycin injections developed skin fibrosis accompanied by elevated IL-33 expression in the dermis. Likewise, we found IL-33 upregulation in human skin fibrosis. Mice with germline deletion of IL-33 receptor (ST2 knockout) showed markedly exacerbated skin fibrosis in association with significantly increased T helper 2 cell to regulatory T-cell ratio in the skin. Mice that lacked ST2 specifically on regulatory T cells (Foxp3Cre,ST2flox/flox) showed significantly worse skin fibrosis, increased T helper 2 to regulatory T cell ratio and IL-13 expression in the skin compared with wild-type mice. Our findings show that IL-33 cytokine signaling to regulatory T cells suppresses skin fibrosis and highlight a potential therapeutic axis to alleviate the debilitating manifestations of systemic sclerosis.