Inhibition of skin fibrosis via regulation of Th17/Treg imbalance in systemic sclerosis

Systemic sclerosis (SSc) is an idiopathic systemic connective tissue disorder characterized by fibrosis of the skin and internal organs, with growing interest in the imbalance between Th17 cells and regulatory T cells (Tregs) in the disease’s pathogenesis. Heligmosomoides polygyrus (Hp), a natural intestinal parasite of mice, is known to induce Tregs in the host. We aimed to investigate the effects of Hp-induced Tregs on bleomycin-induced dermal fibrosis and clarify the role of the Th17/Treg balance in SSc fibrosis. Infection with Hp suppressed the development of bleomycin-induced dermal fibrosis and the infiltration of CD3 ⁺ T cells and CD68 ⁺ macrophages. Flow cytometric analysis revealed that Hp infection increased Tregs and inhibited the induction of bleomycin-induced Th17 cells. Treg depletion nullified these effects, suggesting that Hp-induced Tregs may prevent bleomycin-induced dermal fibrosis and inflammation. Analysis of the intestinal microbiota showed that bacteria positively correlated with Tregs exhibited a negative correlation with Th17 cells and dermal fibrosis in mice. SSc patients with severe fibrosis displayed a distinct microbiota profile. These results suggest that alterations in the intestinal microbiota may contribute to the Th17/Treg imbalance in SSc and its progression. Enhancing Tregs to regulate the Th17/Treg imbalance may present a promising strategy for suppressing fibrosis in SSc.