ROS调控ESCRT-III抑制caspase/gasdermin D介导的中性粒细胞焦亡在银屑病中的作用及机制研究

焦亡是gasdermin介导的细胞裂解死亡，受钙内流启动ESCRT-III依赖的质膜修复负调控；中性粒细胞分泌IL-1β依赖caspase-1/gasdermin D的激活但很少发生焦亡，抑制ROS可促其焦亡。中性粒细胞ROS升高参与银屑病发病，但中性粒细胞焦亡在银屑病中的作用及机制尚不明确。我们前期研究发现银屑病中性粒细胞存在caspase-1/gasdermin D通路的激活。鉴于此，本项目拟以中性粒细胞为研究对象，建立银屑病及基因敲除小鼠模型，研究ROS调控中性粒细胞焦亡及在银屑病中的作用，通过ROS及钙内流检测、LDH及IL-1β释放测量等实验，并通过干预焦亡信号通路及质膜修复，观察对中性粒细胞焦亡、IL-1β释放及银屑病的影响，揭示银屑病中性粒细胞焦亡受ROS调控的分子机制。本项目的实施将为中性粒细胞参与银屑病发病机制提供新的理论和实验依据，为靶向中性粒细胞治疗银屑病提供新思路。

Pyroptosis is a type of lytic cell death mediated by gasdermin, negatively regulated by calcium influx-initiated ESCRT-III-dependent plasma membrane repair. Neutrophils secrete IL-1β, depending on activated caspase-1/gasdermin D but seldom leading to pyroptosis. The inhibition of ROS facilitates neutrophil pyroptosis. The increasing production of ROS in neutrophils is involved in the pathogenesis of psoriasis, however, the role and mechanism of neutrophil pyroptosis in psoriasis is unclear. Our preliminary study found caspase-1/gasdermin D signaling pathway was activated in neutrophils of psoriasis. Herein, this project intends to take neutrophils as the research object, establish mouse models of psoriasis and gene knockout, and study the mechanism of ROS-regulated neutrophil pyroptosis and its role in psoriasis. We will do ROS and calcium influx detection, LDH and IL-1β release measurement and other experiments, and interfere with pyroptosis signal pathway and plasma membrane repair to observe their effects on neutrophil pyroptosis, IL-1β release and psoriasis, and then reveal the molecular mechanism of neutrophil pyroptosis regulated by ROS in psoriasis. The implementation of this project will provide new theoretical and experimental basis for the study of neutrophils participating in the pathogenesis of psoriasis, and new idea for treating psoriasis by targeting neutrophils.