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  3. NLRP3 inflammasome mediates pyroptosis of alveolar macrophages to induce radiation lung injury

NLRP3 inflammasome mediates pyroptosis of alveolar macrophages to induce radiation lung injury

  • J Hazard Mater. 2024 Dec 1:484:136740. doi: 10.1016/j.jhazmat.2024.136740.
Mingwei Zhang 1,  Hailin Lan 1,  Meina Jiang 1,  Minghuan Yang 2,  Hongquan Chen 2,  Shaoli Peng 1,  Xuezhen Wang 1,  Yarui Zhang 1,  Xingxin Huang 3,  Lianhuang Li 4,  Chun Chen 5,  Jinsheng Hong 6
Affiliations

Affiliations

  • 1 Department of Radiotherapy, Cancer Center, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Radiotherapy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital of Fujian Medical University, Fuzhou 350212, China; Key Laboratory of Radiation Biology of Fujian Higher Education Institutions, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
  • 2 Key Laboratory of Radiation Biology of Fujian Higher Education Institutions, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
  • 3 Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, Fuzhou 350007, China.
  • 4 Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, Fuzhou 350007, China. Electronic address: lhli@fjnu.edu.cn.
  • 5 Department of Radiotherapy, Cancer Center, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; School of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122, China. Electronic address: chenchun-0428@163.com.
  • 6 Department of Radiotherapy, Cancer Center, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Department of Radiotherapy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital of Fujian Medical University, Fuzhou 350212, China; Key Laboratory of Radiation Biology of Fujian Higher Education Institutions, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China. Electronic address: 13799375732@fjmu.edu.cn.
PMID: 39642726 DOI: 10.1016/j.jhazmat.2024.136740
Abstract

Alveolar macrophages play a crucial role in maintaining lung homeostasis. However, the mechanisms underlying alveolar macrophage Pyroptosis and inflammasome activation in radiation-induced lung injury remain unclear. In this study, we employed multicolor flow cytometry and single-cell RNA Sequencing to reveal the immune cell and cell death landscape in the tissue microenvironment of radiation-induced lung injury. Additionally, we utilized mass spectrometry, co-immunoprecipitation and Duolink techniques to investigate the core inflammasome responsible for mediating alveolar macrophage Pyroptosis. We noticed that the percentage of alveolar macrophages, T, B and epithelial cells decreased significantly post-irradiation. Notably, the proportional changes in alveolar macrophages closely correlated with Szapiels' pneumonia score. Furthermore, alveolar macrophages emerged as the earliest cell type to initiate Pyroptosis and act as pivotal regulators of cell communication. In vitro and in vivo experiments, we observed a significant increase in NLRP3 binding to the apoptosis-associated speck-like protein in irradiated alveolar macrophages. In vivo, MCC950 effectively inhibited alveolar macrophage Pyroptosis and significantly reducing inflammatory cells recruitment. Subsequently, targeting AM Pyroptosis ultimately inhibit the infiltration of interstitial macrophages and the activation of fibroblasts, decrease collagen deposition and alleviate the severity of radiation-induced lung fibrosis. Targeting alveolar macrophage Pyroptosis and NLRP3 inflammasome activation hold substantial therapeutic potential for mitigating radiation-induced lung injury.

Keywords

Alveolar macrophages; MCC950; NLRP3 inflammasome; Pyroptosis; Radiation-induced lung injury.

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