Inhibitory effect of bleomycin-induced skin fibrosis by regulating the imbalance between Th17 cells and regulatory T cells

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs, vasculopathy and immune dysregulation. There is growing evidence that Imbalance between Th17 and Treg cell subsets plays an important role in the pathogenesis of SSc. Heligmosomoides polygyrus (Hp) infection is known to activate Treg and suppress the symptoms of animal model of various autoimmune diseases. Objective was to elucidate the effects of the activation of Treg cells by Hp infection on bleomycin-induced skin fibrosis in mice and the mechanism of the inhibitory action of fibrosis. We identified that prior infection with Hp significantly inhibited bleomycin-induced skin fibrosis in mice. The number of (alpha)SMA+ myofibroblasts and CD68+ macrophages in lesional skin were significantly reduced by Hp infection. Flow cytometric analysis of lymph nodules revealed that the number of CD4+CD25+Foxp3+ Treg cells increased and Th17 cells decreased in Hp infected mice. Furthermore, depletion of Treg cells reversed the suppression of bleomycin-induced skin fibrosis caused by Hp infection and increased Th17 cells. In addition, intestinal microbiota examination showed a positive correlation between the number of Treg cells and Escherichia, Rikenellaceae, Ruminococcaceae and Akkermansia. Furthermore, we found that SSc patients with diffuse cutaneous type SSc (dcSSc), severe skin sclerosis, digital ulcer (DU), and complications of interstitial lung disease (ILD) have a distinctly different microbiota from healthy individuals. The microbiota in this population was found to be more Enterobacteriaceae and less Bifidobacteriaceae and Ruminococcaceae than other SSc patients and healthy individuals. In conclusion, we demonstrated that the imbalance between Th17 and Treg cells is involved in the pathogenesis of SSc, and improvement of the imbalance may be a new therapeutic target for SSc. In accordance with this aspect, modulation of microbiota may be applicable to a new treatment of SSc patients and further investigation is required.