2. Academic Validation
  3. Crystalline silica-induced macrophage pyroptosis interacting with mitophagy contributes to pulmonary fibrosis via modulating mitochondria homeostasis

Crystalline silica-induced macrophage pyroptosis interacting with mitophagy contributes to pulmonary fibrosis via modulating mitochondria homeostasis

  • J Hazard Mater. 2023 May 3;454:131562. doi: 10.1016/j.jhazmat.2023.131562.
Yungeng Wei 1,  Yichuan You 1,  Jiarui Zhang 2,  Jiaqi Ban 1,  Hui Min 3,  Chao Li 4,  Jie Chen 5
Affiliations

Affiliations

  • 1 Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, Liaoning, China; Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang 110122, Liaoning, China.
  • 2 Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, Liaoning, China; Experimental Teaching Center, School of Public health, China Medical University, Shenyang 110122, Liaoning, China.
  • 3 Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang 110122, Liaoning, China.
  • 4 Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, Liaoning, China; Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang 110122, Liaoning, China. Electronic address: lichao@cmu.edu.cn.
  • 5 Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, Liaoning, China; Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang 110122, Liaoning, China. Electronic address: jchen@cmu.edu.cn.
PMID: 37148789 DOI: 10.1016/j.jhazmat.2023.131562
Abstract

Environmental exposure to crystalline silica (CS) can lead to silicosis. Alveolar macrophages (AMs) play a crucial role in the pathogenesis of silicosis. Previously, we demonstrated that enhancing AMs Mitophagy exerted protective effects on silicosis with a restrained inflammatory response. However, the exact molecular mechanisms are elusive. Pyroptosis and Mitophagy are two different biological processes that determine cell fate. Exploring whether there were interactions or balances between these two processes in AMs would provide new insight into treating silicosis. Here we reported that crystalline silica induced Pyroptosis in silicotic lungs and AMs with apparent mitochondria injury. Notably, we identified a reciprocal inhibitory effect between Mitophagy and Pyroptosis cascades in AMs. By enhancing or diminishing Mitophagy, we demonstrated that PINK1-mediated Mitophagy helped clear damaged mitochondria to negatively regulate CS-induced Pyroptosis. While constraining Pyroptosis cascades by NLRP3, Caspase1, and GSDMD inhibitors, respectively, displayed enhanced PINK1-dependent Mitophagy with lessened CS-injured mitochondria. These observed effects were echoed in the mice with enhanced Mitophagy. Therapeutically, we demonstrated abolishing GSDMD-dependent Pyroptosis by disulfiram attenuated CS-induced silicosis. Collectively, our data demonstrated that macrophage Pyroptosis interacting with Mitophagy contributes to pulmonary fibrosis via modulating mitochondria homeostasis, which may provide potential therapeutic targets.

Keywords

Crystalline silica; Macrophages; Mitophagy; Pulmonary fibrosis; Pyroptosis.

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