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

doi:10.1016/j.jaci.2019.10.008

Particulate matter of 2.5 μm or less in diameter disturbs the balance of T_H17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model

J Allergy Clin Immunol. 2020 Jan;145(1):402-414. doi: 10.1016/j.jaci.2019.10.008. Epub 2019 Oct 21.

Authors

Licheng Sun¹, Jinrong Fu², Sheng-Hao Lin³, Jin-Lyu Sun⁴, Li Xia¹, Ching-Hsiung Lin³, Lijuan Liu⁵, Caiyan Zhang¹, Lan Yang¹, Ping Xue⁶, Xiang Wang⁶, Saihua Huang¹, Xiao Han¹, Hua-Ling Chen⁷, Ming-Shyan Huang⁸, Xiaobo Zhang⁵, Shau-Ku Huang⁹, Yufeng Zhou¹⁰

Affiliations

¹ Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; NHC Key Laboratory of Neonatal Diseases (Fudan University), Shanghai, China.
² Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Respirology Department, Children's Hospital of Fudan University, Shanghai, China.
³ Chest Division, Department of Internal Medicine, Chang-Hua Christian Hospital, Chang-Hua, Taiwan.
⁴ Department of Allergy, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing Key Laboratory of Precision Medicine for Diagnosis and Treatment on Allergic Diseases, Beijing, China.
⁵ Respirology Department, Children's Hospital of Fudan University, Shanghai, China.
⁶ Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁷ National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
⁸ Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
⁹ National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan; Johns Hopkins University School of Medicine, Baltimore, Md; Kaohsiung Medical University, Kaohsiung, Taiwan; Lou-Hu Hospital, Shen-Zhen University, Shen-Zhen, China.
¹⁰ Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; NHC Key Laboratory of Neonatal Diseases (Fudan University), Shanghai, China. Electronic address: yfzhou1@fudan.edu.cn.

PMID: 31647966
DOI: 10.1016/j.jaci.2019.10.008

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 T_H17/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 T_H17 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 T_H17 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 T_H17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on T_H17/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 T_H17/Treg cells.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aspartate Aminotransferase, Cytoplasmic / genetics
Aspartate Aminotransferase, Cytoplasmic / immunology*
Asthma / chemically induced
Asthma / genetics
Asthma / immunology*
Cell Differentiation / drug effects
Cell Differentiation / genetics
Disease Models, Animal
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / immunology*
Mice
Mice, Mutant Strains
Particle Size
Particulate Matter / toxicity*
Receptors, Aryl Hydrocarbon / genetics
Receptors, Aryl Hydrocarbon / immunology
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / pathology
Th17 Cells / immunology*
Th17 Cells / pathology

Substances

Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit
Particulate Matter
Receptors, Aryl Hydrocarbon
Aspartate Aminotransferase, Cytoplasmic
Got1 protein, mouse