Yang Huan, Shi Yanqiang, Liu Huiting, Lin Feiyan, Qiu Biying, Feng Qinglan, Wang Yu, Yang Bin
Dermatology Hospital, Southern Medical University, Guangzhou, 510091, China.
Cell Death Discov. 2022 Apr 8;8(1):183. doi: 10.1038/s41420-022-00970-1.
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.
NLRP3炎性小体和白细胞介素-1β（IL-1β）对硬皮病的发病机制至关重要。然而，作为NLRP3的下游分子且在某些情况下是IL-1β释放所必需的细胞焦亡执行者gasdermin D（GSDMD），在硬皮病中的作用尚未得到充分阐明。在此，我们发现GSDMD在硬皮病患者的皮肤以及博来霉素诱导的小鼠模型中显著上调并被激活。此外，根据苏木精-伊红（HE）染色、Masson染色以及羟脯氨酸含量检测，GSDMD的缺失改善了博来霉素诱导的皮肤纤维化。GSDMD缺乏还损害了巨噬细胞浸润并降低了炎症反应。此外，GSDMD的缺失在体内和体外均减少了辅助性T细胞17（Th17）的分化。总体而言，这些发现首次证明与GSDMD相关的细胞焦亡在硬皮病发病机制中起重要作用。
