Song Meiyue, Wang Jiaxin, Sun Youliang, Pang Junling, Li Xiaona, Liu Yuan, Zhou Yitian, Yang Peiran, Fan Tianhui, Liu Ying, Li Zhaoguo, Qi Xianmei, Li Baicun, Zhang Xinri, Wang Jing, Wang Chen
State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100730, China.
Tsinghua-Peking Center for Life Sciences, Department of Biology, College of Medicine, Tsinghua University, Beijing 100084, China.
Acta Pharm Sin B. 2022 Mar;12(3):1213-1224. doi: 10.1016/j.apsb.2021.10.006. Epub 2021 Oct 15.
Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide, but the molecular basis underlying its development remains unclear. An accumulating body of evidence supports gasdermin D (GSDMD)-mediated pyroptosis as a key component in the development of various pulmonary diseases. However, there is little experimental evidence connecting silicosis and GSDMD-driven pyroptosis. In this work, we investigated the role of GSDMD-mediated pyroptosis in silicosis. Single-cell RNA sequencing of healthy and silicosis human and murine lung tissues indicated that GSDMD-induced pyroptosis in macrophages was relevant to silicosis progression. Through microscopy we then observed morphological alterations of pyroptosis in macrophages treated with silica. Measurement of interleukin-1 release, lactic dehydrogenase activity, and real-time propidium iodide staining further revealed that silica induced pyroptosis of macrophages. Additionally, we verified that both canonical (caspase-1-mediated) and non-canonical (caspase-4/5/11-mediated) signaling pathways mediated silica-induced pyroptosis activation, and . Notably, knockout mice exhibited dramatically alleviated silicosis phenotypes, which highlighted the pivotal role of pyroptosis in this disease. Taken together, our results demonstrated that macrophages underwent GSDMD-dependent pyroptosis in silicosis and inhibition of this process could serve as a viable clinical strategy for mitigating silicosis.
矽肺是全球职业病相关发病和死亡的主要原因，但其发病的分子基础仍不清楚。越来越多的证据支持gasdermin D（GSDMD）介导的细胞焦亡是各种肺部疾病发展的关键组成部分。然而，几乎没有实验证据将矽肺与GSDMD驱动的细胞焦亡联系起来。在这项工作中，我们研究了GSDMD介导的细胞焦亡在矽肺中的作用。对健康和矽肺患者及小鼠肺组织进行单细胞RNA测序表明，巨噬细胞中GSDMD诱导的细胞焦亡与矽肺进展相关。然后，通过显微镜观察了用二氧化硅处理的巨噬细胞中细胞焦亡的形态学变化。白细胞介素-1释放、乳酸脱氢酶活性的测定以及碘化丙啶实时染色进一步表明二氧化硅诱导了巨噬细胞的细胞焦亡。此外，我们证实经典（半胱天冬酶-1介导）和非经典（半胱天冬酶-4/5/11介导）信号通路均介导了二氧化硅诱导的细胞焦亡激活，并且。值得注意的是，基因敲除小鼠的矽肺表型显著减轻，这突出了细胞焦亡在该疾病中的关键作用。综上所述，我们的结果表明，在矽肺中巨噬细胞发生了依赖GSDMD的细胞焦亡，抑制这一过程可能是减轻矽肺的一种可行的临床策略。
