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  3. The role of PP2A /NLRP3 signaling pathway in ambient particulate matter 2.5 induced lung injury

The role of PP2A /NLRP3 signaling pathway in ambient particulate matter 2.5 induced lung injury

  • Chemosphere. 2022 Nov;307(Pt 2):135794. doi: 10.1016/j.chemosphere.2022.135794.
Bin Han 1,  Qingping Liu 2,  Xuan Su 3,  Lixiao Zhou 4,  Boyuan Zhang 5,  Hui Kang 6,  Jie Ning 7,  Chen Li 8,  Bo Zhao 9,  Yujie Niu 10,  Wen Chen 11,  Liping Chen 12,  Rong Zhang 13
Affiliations

Affiliations

  • 1 Department of Toxicology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 2 Department of Toxicology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 3 Department of Toxicology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 4 Department of Toxicology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 5 Department of Toxicology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 6 Occupational Health and Environmental Health, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 7 Department of Toxicology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 8 Department of Toxicology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 9 Department of Laboratory Diagnosis, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 10 Occupational Health and Environmental Health, Hebei Medical University, Shijiazhuang, 050017, Hebei, China; Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
  • 11 Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: [email protected].
  • 12 Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: [email protected].
  • 13 Department of Toxicology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China; Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. Electronic address: [email protected].
PMID: 35926746 DOI: 10.1016/j.chemosphere.2022.135794
Abstract

Ambient particulate matter 2.5 (PM2.5) exposure has been linked to pulmonary fibrosis. However, the key signaling pathways remained unclear. In the present study, we applied a mouse model with myeloid-specific deletion of Ppp2r1a gene (encoding protein Phosphatase 2 A (PP2A) A subunit) to identify the key signaling pathways involved in PM2.5-induced pulmonary fibrosis. PP2A Aα-/- homozygote mice and matched wild-type (WT) littermates were exposed to filtered air (FA), unfiltered air (UA), and concentrated PM2.5 (CA) in a real-ambient PM exposure system for 8 weeks and 16 weeks, respectively. The mice exposed to PM2.5 displayed a progressive inflammation and pulmonary fibrosis. Moreover, the expressions of NLRP3, pro-caspase-1, Caspase-1, ASC and IL-1β were increased in mice lung following PM2.5 exposure, indicating PM2.5 exposure caused pulmonary inflammation by the NLRP3 pathways activation. Furthermore, the effects of PM exposure on pulmonary inflammation, pulmonary fibrosis, oxidative stress, and pulmonary function damage were significantly enhanced in PP2A-/- mice compared to WT mice, indicating the role of PP2A in the regulation of pulmonary injury induced by PM exposure. In vitro study confirmed that PP2A was involved in the PM2.5-induced inflammation response and NLRP3 inflammasome activation. Importantly, we identified PP2A regulated the activation of NLRP3 pathways by direct dephosphorylating IRE1α in response to PM2.5 exposure. Taken together, our results demonstrated that PP2A-IRE1α-NLRP3 signaling pathway played a crucial role in regulating the inflammation response, triggering the lung fibrogenesis upon PM2.5 exposure. Our findings provide new insights into regulatory role of PP2A in human diseases upon the PM exposure.

Keywords

IRE1α; Inflammasomes; PM(2.5); PP2A; Pulmonary fibrosis.

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