Original articles
Meiyue Song, Jiaxin Wang, Youliang Sun, Junling Pang, Xiaona Li, Yuan Liu, Yitian Zhou, Peiran Yang, Tianhui Fan, Ying Liu, Zhaoguo Li, Xianmei Qi, Baicun Li, Xinri Zhang, Jing Wang, Chen Wang. Inhibition of gasdermin D-dependent pyroptosis attenuates the progression of silica-induced pulmonary inflammation and fibrosis[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1213-1224

Inhibition of gasdermin D-dependent pyroptosis attenuates the progression of silica-induced pulmonary inflammation and fibrosis
Meiyue Songa, Jiaxin Wangb, Youliang Sunc, Junling Panga, Xiaona Lia, Yuan Liud,e,f, Yitian Zhouf,g, Peiran Yanga, Tianhui Fana, Ying Liua, Zhaoguo Lih, Xianmei Qia, Baicun Lia, Xinri Zhangi, Jing Wanga, Chen Wanga,d,e
a. 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;
b. Tsinghua-Peking Center for Life Sciences, Department of Biology, College of Medicine, Tsinghua University, Beijing 100084, China;
c. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China;
d. Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China;
e. National Clinical Research Center for Respiratory Diseases, Beijing 100029, China;
f. Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China;
g. Peking Union Medical College, MD Program, Beijing 100730, China;
h. Department of Respiratory, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China;
i. Department of Pulmonary and Critical Care Medicine, the First Hospital of Shanxi Medical University, Taiyuan 030001, China
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-1β 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, 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.
Key words:    Silicosis    Gasdermin D    Pyroptosis    Macrophage    Pulmonary fibrosis   
Received: 2021-06-28     Revised: 2021-08-12
DOI: 10.1016/j.apsb.2021.10.006
Funds: This study was supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS; Nos. 2021-1-I2M-049 and 2018-I2M-1-001, China), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (Nos. 2019RC330001 and 2021RC310002, China) and National Natural Science Foundation of China (No. 82090010). Special thanks to Prof. Feng Shao for his generous experimental assistance.
Corresponding author: Xinri Zhang,E-mai:ykdzxr61@163.com;Jing Wang,E-mai:wangjing@ibms.pumc.edu.cn     Email:ykdzxr61@163.com;wangjing@ibms.pumc.edu.cn
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Meiyue Song
Jiaxin Wang
Youliang Sun
Junling Pang
Xiaona Li
Yuan Liu
Yitian Zhou
Peiran Yang
Tianhui Fan
Ying Liu
Zhaoguo Li
Xianmei Qi
Baicun Li
Xinri Zhang
Jing Wang
Chen Wang

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