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NLRP3 inflammasome activation determines the fibrogenic potential of PM2.5 air pollution particles in the lung

Wei Cao, Xiang Wang, Jiulong Li, Ming Yan, Chong Hyun Chang, Joshua Kim, Jinhong Jiang, Yu-Pei Liao, Shannon Tseng, Sydney Kusumoputro, Candice Lau, Marissa Huang, Pengli Han, Pengju Lu, Tian Xia
Journal of environmental sciences (China) 2022 v.111 pp. 429-441
air pollution, cathepsin B, collagen, cytotoxicity, epithelium, fibrosis, humans, inflammasomes, inflammation, lungs, macrophages, particulates, pulmonary fibrosis, China
Airborne fine particulate matter (PM₂.₅) is known to cause respiratory inflammation such as chronic obstructive pulmonary disease and lung fibrosis. NLRP3 inflammasome activation has been implicated in these diseases; however, due to the complexity in PM₂.₅ compositions, it is difficult to differentiate the roles of the components in triggering this pathway. We collected eight real-life PM₂.₅ samples for a comparative analysis of their effects on NLRP3 inflammasome activation and lung fibrosis. In vitro assays showed that although the PM₂.₅ particles did not induce significant cytotoxicity at the dose range of 12.5 to 100 µg/mL, they induced potent TNF-α and IL-1β production in PMA differentiated THP-1 human macrophages and TGF-β1 production in BEAS-2B human bronchial epithelial cells. At the dose of 100 µg/mL, PM₂.₅ induced NLRP3 inflammasome activation by inducing lysosomal damage and cathepsin B release, leading to IL-1β production. This was confirmed by using NLRP3- and ASC-deficient cells as well as a cathepsin B inhibitor, ca-074 ME. Administration of PM₂.₅ via oropharyngeal aspiration at 2 mg/kg induced significant TGF-β1 production in the bronchoalveolar lavage fluid and collagen deposition in the lung at 21 days post-exposure, suggesting PM₂.₅ has the potential to induce pulmonary fibrosis. The ranking of in vitro IL-1β production correlates well with the in vivo total cell count, TGF-β1 production, and collagen deposition. In summary, we demonstrate that the PM₂.₅ is capable of inducing NLRP3 inflammasome activation, which triggers a series of cellular responses in the lung to induce fibrosis.