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 T17/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 T17 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 T17 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 T17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on T17/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 T17/Treg cells.
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| http://dx.doi.org/10.1016/j.jaci.2019.10.008 | DOI Listing |
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