IL-33/ST2 axis contributes to the dermal fibrosis of systemic sclerosis via promoting fibroblasts activation

Background: Systemic sclerosis (SSc) is a chronic immune-mediated rheumatic disease that is characterized by fibrosis of the skin and internal organs. Interleukin-33 (IL-33) has been recently implicated in several autoimmune diseases through its receptor ST2. Objective: The aim of this study was to investigate the role and underlying mechanism of IL-33/ST2 axis in the fibrotic disorder of SSc. Methods: The bleomycin (BLM)-induced fibrotic skin and skin biopsies of SSc patients were used to detect the expression of IL-33 and ST2. Human dermal fibroblasts were stimulated with recombinant IL-33(rIL-33) protein and their activation, proliferation and migration were assessed. The role of IL-33/ST2 axis was in-vestigated in mouse fibrosis model via histologically assessing skin fibrosis after IL-33 gene knockout. ST2 neutralizing antibody treatment was also obtained to estimate the possible effect. Results: The number IL-33(+) cells and ST2(+) cells were increased in the lesion skin of SSc patients and BLMinduced mouse. Human skin fibroblasts highly expressed ST2 protein, and the proliferation, migration, and collagen expression were significantly elevated after rIL-33 stimulation, accompanied by the activation of MAPKs and NF-kappa B pathways. The severity of skin fibrosis was significantly reduced in il33(-/-) mice compared with WT mice. Blockade of IL-33 receptor using an anti-ST2 neutralizing antibody effectively ameliorated the skin fibrosis. Conclusion: These data indicate that IL-33/ST2 axis contributes to the fibrotic skin injury of SSc via promoting fibroblasts activation, and IL-33/ST2 blockade might serve as a novel strategy to inhibit the fibrosis progression in patients of SSc. (C) 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.