FOXA1-TET1 Mediate the DNA Hypomethylation of IL-4 Is Involved in Dust Fall PM2.5 Induced Lung Inflammation.

Abstract

PM_2.5 has been linked to a variety of lung diseases. The objective of this study was to investigate the mechanism of lung inflammation caused by acute exposure to PM_2.5 from the perspective of DNA methylation. Sprague-Dawley male rats were exposed to different concentrations of PM_2.5 by non-exposure intratracheal instillation every other day for 3 times. Chemically modified si-Foxa1, si-Tet1, and si-NC were administered via the intratracheal instillation, followed by exposure to a medium concentration of PM_2.5. Fourteen days following the final exposure, serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for the appropriate tests. Acute exposure to PM_2.5 resulted in infiltration of inflammatory cells and destruction of the alveolar structure. The levels of IL-4 and eotaxin-1 in serum and BALF were increased, while the levels of interferon-γ (IFN-γ) were decreased. In lung tissues, there was a decrease in the whole genome 5-mC and an increase in 5-hmC. The methylation level of the interleukin-4 (IL-4) DNA promoter CpG islands decreased, accompanied by an increase in the mRNA level. The protein expression of Forkhead box A1 (FOXA1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) was upregulated. Downregulation of FOXA1 and TET1 levels reversed those changes. PM_2.5 induced the upregulation of FOXA1 and TET1 protein expression, which subsequently affected the DNA methylation levels of IL-4. This, in turn, promoted the release of IL-4 and led to pulmonary inflammation. This study provides insights into the potential DNA methylation regulatory mechanisms underlying lung inflammation induced by acute PM_2.5 exposure.