Pyroptosis executor gasdermin D plays a key role in scleroderma and bleomycin-induced skin fibrosis

The NLRP3 inflammasome and IL-1β are essential for scleroderma pathogenesis. Nevertheless, the role of pyroptosis executor gasdermin D(GSDMD), which is a downstream molecule of NLRP3 and is required for IL-1β release in some situations, has not yet been well elucidated in scleroderma. Here, we found that GSDMD was significantly up-regulated and activated in the skin of scleroderma patients and bleomycin-induced mouse model. What’s more, the ablation of GSDMD ameliorates bleomycin-induced skin fibrosis according to HE staining, Masson staining and the detection of hydroxyproline contents. GSDMD deficiency also impaired macrophages infiltration and reduced inflammation response. Furthermore, the loss of GSDMD reduced Th17 differentiation in vivo and in vitro. Collectively, these findings provide the first demonstration that GSDMD related pyroptosis plays an important role in scleroderma pathogenesis.