Particulate matter of 2.5 μm or less in diameter disturbs the balance of TH17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model

Licheng Sun, Jinrong Fu, Sheng Hao Lin, Jin Lyu Sun, Li Xia, Ching Hsiung Lin, Lijuan Liu, Caiyan Zhang, Lan Yang, Ping Xue, Xiang Wang, Saihua Huang, Xiao Han, Hua Ling Chen, Ming Shyan Huang, Xiaobo Zhang, Shau Ku Huang, Yufeng Zhou

Research output: Contribution to journalArticle

Abstract

Background: Epidemiologic evidence suggests that exposure to particulate matter of 2.5 μm or less in diameter (PM2.5) aggravates asthma. Objective: We sought to investigate the underlying mechanisms between PM2.5 exposure and asthma severity. Methods: The relationship between PM2.5 exposure and asthma severity was investigated in an asthma model with CD4+ T cell–specific aryl hydrocarbon receptor (AhR)–null mice. Effects of PM2.5 and polycyclic aromatic hydrocarbons (PAHs) on differentiation of TH17/regulatory T (Treg) cells were investigated by using flow cytometry and quantitative RT-PCR. Mechanisms were investigated by using mRNA sequencing, chromatin immunoprecipitation, bisulfite sequencing, and glycolysis rates. Results: PM2.5 impaired differentiation of Treg cells, promoted differentiation of TH17 cells, and aggravated asthma in an AhR-dependent manner. PM2.5 and one of its prominent PAHs, indeno[1,2,3-cd]pyrene (IP), promoted differentiation of TH17 cells by upregulating hypoxia-inducible factor 1α expression and enhancing glycolysis through AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase 1 (Got1) expression through AhRs and accumulation of 2-hydroxyglutarate, which inhibited ten-eleven translocation methylcytosine dioxygenase 2 activity, resulting in hypermethylation in the forkhead box P3 locus and impaired differentiation of Treg cells. A GOT1 inhibitor, (aminooxy)acetic acid, ameliorated asthma by shifting differentiation of TH17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on TH17/Treg cell imbalance were noted in human T cells, and in a case-control design PAH exposure appeared to be a potential risk factor for asthma. Conclusions: The AhR–hypoxia-inducible factor 1α and AhR-GOT1 molecular pathways mediate pulmonary responses on exposure to PM2.5 through their ability to disturb the balance of TH17/Treg cells.

Original languageEnglish
Pages (from-to)402-414
Number of pages13
JournalJournal of Allergy and Clinical Immunology
Volume145
Issue number1
DOIs
Publication statusPublished - Jan 1 2020
Externally publishedYes

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Keywords

  • aryl hydrocarbon receptors
  • Asthma
  • DNA methylation
  • glycolysis
  • particulate matter of 2.5 μm or less in diameter
  • T-cell differentiation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Sun, L., Fu, J., Lin, S. H., Sun, J. L., Xia, L., Lin, C. H., Liu, L., Zhang, C., Yang, L., Xue, P., Wang, X., Huang, S., Han, X., Chen, H. L., Huang, M. S., Zhang, X., Huang, S. K., & Zhou, Y. (2020). Particulate matter of 2.5 μm or less in diameter disturbs the balance of TH17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model. Journal of Allergy and Clinical Immunology, 145(1), 402-414. https://doi.org/10.1016/j.jaci.2019.10.008