Inhibition of gasdermin D-dependent pyroptosis attenuates the progression of silica-induced pulmonary inflammation and fibrosis.
10.1016/j.apsb.2021.10.006
- Author:
Meiyue SONG
1
;
Jiaxin WANG
2
;
Youliang SUN
3
;
Junling PANG
1
;
Xiaona LI
1
;
Yuan LIU
4
;
Yitian ZHOU
5
;
Peiran YANG
1
;
Tianhui FAN
1
;
Ying LIU
1
;
Zhaoguo LI
6
;
Xianmei QI
1
;
Baicun LI
1
;
Xinri ZHANG
7
;
Jing WANG
1
;
Chen WANG
1
Author Information
1. 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.
2. Tsinghua-Peking Center for Life Sciences, Department of Biology, College of Medicine, Tsinghua University, Beijing 100084, China.
3. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
4. Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China.
5. Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
6. Department of Respiratory, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
7. Department of Pulmonary and Critical Care Medicine, the First Hospital of Shanxi Medical University, Taiyuan 030001, China.
- Publication Type:Journal Article
- Keywords:
Gasdermin D;
Macrophage;
Pulmonary fibrosis;
Pyroptosis;
Silicosis
- From:
Acta Pharmaceutica Sinica B
2022;12(3):1213-1224
- CountryChina
- Language:English
-
Abstract:
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.
