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

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.

• Authors: Shen Chen, Liping Chen, Lizhu Ye, Yue Jiang, Qiong Li, Haiyan Zhang, Rui Zhang, Huiyao Li, Dianke Yu, Rong Zhang, Yujie Niu, Qun Zhao, Jianhui Liu, Gangfeng Ouyang, Michael Aschner, Yuxin Zheng, Lihua Zhang, Wen Chen, Daochuan Li
• Journal: Journal of hazardous materials (J Hazard Mater) Vol. 424 Issue Pt C Pg. 127624 (02 15 2022) ISSN: 1873-3336 [Electronic] Netherlands
• PMID: 34740159 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Particulate Matter
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Protein Phosphatase 2

Topics

• Animals
• Lung Injury (chemically induced)
• Macrophages, Alveolar
• Mice
• Particulate Matter (toxicity)
• Phosphorylation
• Protein Phosphatase 2 (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (genetics, metabolism)
• TOR Serine-Threonine Kinases (genetics, metabolism)