PM2.5 disturbs the balance of Th17/Treg cells by targeting Got1 and HIF-1α in an asthma model.

Epidemiologic evidence suggests that exposure to particulate matter ≤2.5 μm (PM2.5) aggravates asthma.Investigate the underlying mechanisms between PM2.5 exposure and asthma severity.

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-helper 17/T-regulatory (Th17/T_reg) cells were investigated by flow cytometry and quantitative reverse-transcription polymerase chain reaction. Mechanisms were investigated by mRNA sequencing, chromatin immunoprecipitation, bisulfite sequencing and glycolysis rates.

PM2.5 impaired differentiation of T_reg 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 up-regulating hypoxia-inducible factor-1α expression and enhancing glycolysis via AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase (Got)1 expression via AhRs and accumulation of R-2-hydroxyglutarate, which inhibited ten-eleven translocation methylcytosine dioxygenase-2 activity, resulting in hypermethylation in the forkhead box p3 locus and impaired differentiation of T_reg cells. A Got1 inhibitor, (aminooxy)acetic acid, ameliorated asthma by shifting differentiation of Th17 cells to T_reg cells. Similar regulatory effects of exposure to PM2.5 or IP on Th17/T_reg imbalance were noted in human T cells and, in a case-control design, PAH exposure appeared to be a potential risk factor for asthma.

The molecular pathways AhR-HIF-1α and AhR-Got1 mediate pulmonary responses upon exposure to PM2.5 through their ability to disturb the balance of Th17/T_reg cells.