PM2.5 exposure deteriorates Th1/Th2 balance in pediatric asthma by downregulating ALKBH5 and enhancing SRSF1 m6A methylation.

Abstract

Accumulating evidence has shown that long-term exposure to particulate matter with aerodynamic diameter of less than 2.5 μm (PM2.5) causes Th1/Th2 imbalance and increases the risk of allergic asthma (AA) in children. However, the mechanism underlying such effect remains elusive. Here, an AA mouse model was developed by intranasal administration of ovalbumin (OVA) and uncovered that OVA-sensitized mice exhibited pathological damage of lung tissues, mucus production, augmented serum IgE levels, enhanced Th2 cells and associated cytokine levels, and diminished Th1 cells and associated cytokine levels. Meanwhile, OVA induction led to upregulation of SRSF1 in mice. Moreover, shRNA-mediated knockdown of SRSF1 suppressed AA and Th1/Th2 imbalance in OVA-sensitized mice. After PM2.5 exposure, AA and Th1/Th2 imbalance were exacerbated and SRSF1 expression was increased in OVA-sensitized mice. Mechanistic experiments demonstrated that PM2.5-mediated inhibition of ALKBH5 expression augmented SRSF1 m6A modification in human bronchial epithelial cells treated with house dust mite. In this process, the m6A-reading protein YTHDF1 bound to SRSF1 mRNA and increased its stability. Furthermore, ALKBH5 overexpression neutralized PM2.5-aggravated Th1/Th2 imbalance in OVA-sensitized mice. Altogether, PM2.5 fosters Th1/Th2 imbalance in pediatric asthma by increasing SRSF1 m6A methylation through ALKBH5 downregulation.