Traffic-related PM and Diverse Constituents Disturb the Balance of Th17/Treg Cells by STAT3/RORγt-STAT5/Foxp3 Signaling Pathway in a Rat Model of Asthma

Water-soluble ions (WSI) and organic extract (OE) in traffic-related particulate matter with aerodynamic diameters ≤ 2.5 μm (TRPM) are potential risk factors for asthma exacerbation. Although CD4 T lymphocytes mediated immune response is involved in the pathogenesis of asthma, the effect of WSI-TRPM and OE-TRPM on the balance of Th17/Treg cells in asthma remains poorly understood. In this study, the ovalbumin (OVA)-sensitized rats were repeatedly exposure to TRPM (3 mg/kg·bw), WSI-TRPM (1.8 mg/kg·bw, 7.2 mg/kg·bw) and OE-TRPM (0.6 mg/kg·bw, 2.4 mg/kg·bw) every three days for five times. The inflammation response and hyperemia edema were observed in the lung and trachea tissues. DNA methylation levels of STAT3 and RORγt genes in rats with WSI-TRPM and OE-TRPM treatment were decreased. DNA methylation level in STAT5 gene tended to decrease, with no change observed on Foxp3 expression. WSI-TRPM and OE-TRPM enhanced the mRNA and protein expression of STAT3 and RORγt while inhibited the expression of STAT5 and Foxp3, which may contribute to the imbalance of Th17/Treg cells (P < 0.05). More importantly, recovered balance of Th17/Treg cell subsets, upregulated p-STAT5 and Foxp3 expression and reduced p-STAT3 and RORγt levels were observed after 5-Aza treatment. Our results demonstrate that the STAT3/RORγt-STAT5/Foxp3 signaling pathway is involved in asthma exacerbation induced by WSI-TRPM and OE-TRPM through disrupting the balance of Th17/Treg cells. The alteration of DNA methylation of STAT3, STAT5, and RORγt genes may be involved in asthma exacerbation as well.