Inhibition of gasdermin D-dependent pyroptosis attenuates the progression of silica-induced pulmonary inflammation and fibrosis

作者：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

来源：Acta Pharmaceutica Sinica B, 2022, 12(3): 1213-1224.

DOI：10.1016/j.apsb.2021.10.006

• Silicosis
• Gasdermin D
• Pyroptosis
• Macrophage
• Pulmonary fibrosis

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 beta 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-l-mediated) and non-canonical (caspase-4/5/11-mediated) signaling pathways mediated silica-induced pyroptosis activation, in vivo and in vitro. Notably, Gsdmd 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.

• 单位
  1; 中国医学科学院; 哈尔滨医科大学; 中国医学科学院北京协和医院; 清华大学