期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 145, 期 1, 页码 402-414出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2019.10.008
关键词
Asthma; particulate matter of 2.5 mu m or less in diameter; aryl hydrocarbon receptors; T-cell differentiation; glycolysis; DNA methylation
资金
- National Key R&D Program of China [2016YFC1305102]
- National Natural Science Foundation of China [81671561, 81974248, 81900751]
- 1000 Young Talents Plan Program of China
- Fudan University
- International Joint Laboratory Program of National Children's Medical Center [EK1125180109]
- Program for Outstanding Medical Academic Leader [2019LJ19]
- Shanghai Municipal Planning Commission of Science and Research Fund [201740065, 20174Y0079]
- Shanghai Pujiang Program [16PJ1401600]
- Shanghai Committee of Science and Technology [19ZR1406400, 18411951700]
- National Health Research Institutes, Taiwan [EOPP10-014, EOSP07-014]
- Shenzhen Science and Technology Peacock Team Project [KQTD20170331145453160]
- Key projects of Beijing Natural Science Foundation [7191008]
- Kaohsiung Medical University The Talent Plan, Taiwan [106KMUOR04]
- Fudan Children's Hospital
Background: Epidemiologic evidence suggests that exposure to particulate matter of 2.5 mu m 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(H)17/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(H)17 cells, and aggravated asthma in an AhRdependent manner. PM2.5 and one of its prominent PAHs, indeno[1,2,3-cd]pyrene (IP), promoted differentiation of T(H)17 cells by upregulating hypoxia-inducible factor 1 proportional to 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(H)17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on T(H)17/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 1 proportional to and AhRGOT1 molecular pathways mediate pulmonary responses on exposure to PM2.5 through their ability to disturb the balance of T(H)17/Treg cells.
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