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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: PP2A-mTOR-p70S6K/4E-BP1 axis regulates M1 polarization of pulmonary macrophages and promotes ambient particulate matter induced mouse lung injury.

Authors: Chen, Shen; Chen, Liping; Ye, Lizhu; Jiang, Yue; Li, Qiong; Zhang, Haiyan; Zhang, Rui; Li, Huiyao; Yu, Dianke; Zhang, Rong; Niu, Yujie; Zhao, Qun; Liu, Jianhui; Ouyang, Gangfeng; Aschner, Michael; Zheng, Yuxin; Zhang, Lihua; Chen, Wen; Li, Daochuan

Published In J Hazard Mater, (2022 02 15)

Abstract: To identify key signaling pathways involved in ambient particulate matter (PM)-induced pulmonary injury, we generated a mouse model with myeloid-specific deletion of Ppp2r1a gene (encoding protein phosphatase 2 A (PP2A) A subunit), and conducted experiments in a real-ambient PM exposure system. PP2A Aα-/- homozygote (Aα HO) mice and matched wild-type (WT) littermates were exposed to PM over 3-week and 6-week. The effects of PM exposure on pulmonary inflammation, oxidative stress, and apoptosis were significantly enhanced in Aα HO compared to WT mice. The number of pulmonary macrophages increased by 74.8~88.0% and enhanced M1 polarization appeared in Aα HO mice upon PM exposure. Secretion of M1 macrophage-related inflammatory cytokines was significantly increased in Aα HO vs. WT mice following PM exposure. Moreover, we demonstrated that PP2A-B56α holoenzyme regulated M1 polarization and that the mTOR signaling pathway mediated the persistent M1 polarization upon PM2.5 exposure. Importantly, PP2A-B56α holoenzyme was shown to complex with mTOR/p70S6K/4E-BP1, and suppression of B56α led to enhanced phosphorylation of mTOR, p70S6K, and 4E-BP1. These observations demonstrate that the PP2A-mTOR-p70S6K/4E-BP1 signaling is a critical pathway in mediating macrophage M1 polarization, which contributes to PM-induced pulmonary injury.

PubMed ID: 34740159 Exiting the NIEHS site

MeSH Terms: Animals; Lung Injury*/chemically induced; Macrophages, Alveolar; Mice; Particulate Matter/toxicity; Phosphorylation; Protein Phosphatase 2/metabolism; Ribosomal Protein S6 Kinases, 70-kDa*/genetics; Ribosomal Protein S6 Kinases, 70-kDa*/metabolism; TOR Serine-Threonine Kinases/genetics; TOR Serine-Threonine Kinases/metabolism

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