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Crystalline silica induces macrophage necrosis and causes subsequent acute pulmonary neutrophilic inflammation

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Abstract

Crystalline silica (CS), an airborne particulate, is a major global occupational health hazard. While it is known as an important pathogenic factor in many severe lung diseases, the underlying mechanisms of its toxicity are still unclear. In the present study, we found that intra-tracheal instillation of CS caused rapid emergence of necrotic alveolar macrophages. Cell necrosis was a consequence of the release of cathepsin B in CS-treated macrophages, which caused dysfunction of the mitochondrial membrane. Damage to mitochondria disrupted Na+/K+ ATPase activity in macrophages, leading to intracellular sodium overload and the subsequent cell necrosis. Further studies indicate that CS-induced macrophage necrosis and the subsequent release of mitochondrial DNA could trigger the recruitment of neutrophils in the lung, which was regulated by the TLR9 signaling pathway. In conclusion, our results suggest a novel mechanism whereby CS leads to rapid macrophage necrosis through cathepsin B release, following the leakage of mitochondrial DNA as a key event in the induction of pulmonary neutrophilic inflammation. This study has important implications for the early prevention and treatment of diseases induced by CS.

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Funding

This work was supported by Sichuan Science and Technology Program (No. 2020YFS0217). This work was supported by the full-time postdoctoral research and development fund of Sichuan University (No. 20826041D4048). This work was supported by the full-time postdoctoral research and development fund of West China Hospital of Sichuan University (No. 2020HXBH059). This work is supported by the National Key Research and Development Program of China (No. 2016YFA0201402), the National Natural Science Foundation of China (No. 81602492), and by the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No. 2018ZX09733001).

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  1. Wen Nie and Tianxia Lan contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People’s Republic of China

    Wen Nie, Tianxia Lan, Xia Yuan, Min Luo, Guobo Shen, Jiayun Yu & Xiawei Wei

  2. Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China

    Wen Nie

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  1. Wen Nie
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Correspondence to Xiawei Wei.

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Nie, W., Lan, T., Yuan, X. et al. Crystalline silica induces macrophage necrosis and causes subsequent acute pulmonary neutrophilic inflammation. Cell Biol Toxicol 38, 591–609 (2022). https://doi.org/10.1007/s10565-021-09620-1

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