2. Academic Validation
  3. Glycolytic reprogramming governs crystalline silica-induced pyroptosis and inflammation through promoting lactylation modification

Glycolytic reprogramming governs crystalline silica-induced pyroptosis and inflammation through promoting lactylation modification

  • Ecotoxicol Environ Saf. 2024 Sep 15:283:116952. doi: 10.1016/j.ecoenv.2024.116952.
Xiaojie You 1,  Yujia Xie 1,  Qiyou Tan 1,  Chao Zhou 2,  Pei Gu 3,  Yingdie Zhang 4,  Shiyu Yang 1,  Haoyu Yin 1,  Bingxin Shang 1,  Yuxin Yao 1,  Dongming Wang 1,  Jixuan Ma 1,  Weihong Chen 5,  Xiaoju Zhang 6
Affiliations

Affiliations

  • 1 Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou 450053, China.
  • 3 The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
  • 4 Longgang Central Hospital, Shenzhen 518100, China.
  • 5 Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: wchen@mails.tjmu.edu.cn.
  • 6 Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou 450053, China. Electronic address: zhangxiaoju@zzu.edu.cn.
PMID: 39217895 DOI: 10.1016/j.ecoenv.2024.116952
Abstract

Prolonged inhalation of environmental crystalline silica (CS) can cause silicosis, characterized by persistent pulmonary inflammation and irreversible fibrosis, but the mechanism has not been elucidated. To uncover the role and underlying mechanism of glycolytic reprogramming in CS-induced pulmonary inflammation, the mouse silicosis models and glycolysis inhibition models were established in vivo. And the CS-induced macrophage activation models were utilized to further explore the underlying mechanism in vitro. The results showed that CS induced lung inflammation accompanied by glycolytic reprogramming and Pyroptosis. The application of glycolysis inhibitor (2-DG) suppressed CS-induced Pyroptosis and alleviated lung inflammation. In vitro, 2-DG effectively impeded CS-induced macrophage Pyroptosis and inflammatory response. Mechanistically, 2-DG suppressed Pyroptosis by inhibiting NLRP3 inflammasome activation both in vivo and in vitro. Furtherly, metabolite lactate facilitated NLRP3-dependent Pyroptosis synergistically with CS particles, while blocking the source of lactate largely alleviated NLRP3 inflammasome activation and subsequent Pyroptosis triggered by CS. More profoundly, the increment of lactate induced by CS might drive NLRP3-dependent Pyroptosis by increasing histone lactylation levels. In conclusion, our findings demonstrated inhibiting glycolytic reprogramming could alleviate CS-induced inflammatory response through suppressing NLRP3 -dependent Pyroptosis. Increased glycolytic metabolite lactate and protein lactylation modifications might represent significant mechanisms during CS-induced NLRP3 activation and macrophage Pyroptosis.

Keywords

Crystalline silica; Glycolytic reprogramming; Lactate; Lactylation; Lung inflammation; Pyroptosis.

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