Urban airborne PM2.5 induces pulmonary fibrosis through triggering glycolysis and subsequent modification of histone lactylation in macrophages

Abstract

Airborne fine particulate matter (PM_2.5) can cause pulmonary inflammation and even fibrosis, however, the underlying molecular mechanisms of the pathogenesis of PM_2.5 exposure have not been fully appreciated. In the present study, we explored the dynamics of glycolysis and modification of histone lactylation in macrophages induced by PM_2.5-exposure in both in vivo and in vitro models. Male C57BL/6 J mice were anesthetized and administrated with PM_2.5 by intratracheal instillation once every other day for 4 weeks. Mouse RAW264.7 macrophages and alveolar epithelial MLE-12 cells were treated with PM_2.5 for 24 h. We found that PM_2.5 significantly increased lactate dehydrogenase (LDH) activities and lactate contents, and up-regulated the mRNA expression of key glycolytic enzymes in the lungs and bronchoalveolar lavage fluids of mice. Moreover, PM_2.5 increased the levels of histone lactylation in both PM_2.5-exposed lungs and RAW264.7 cells. The pro-fibrotic cytokines secreted from PM_2.5-treated RAW264.7 cells triggered epithelial-mesenchymal transition (EMT) in MLE-12 cells through activating transforming growth factor-β (TGF-β)/Smad2/3 and VEGFA/ERK pathways. In contrast, LDHA inhibitor (GNE-140) pretreatment effectively alleviated PM_2.5-induced pulmonary inflammation and fibrosis via inhibiting glycolysis and subsequent modification of histone lactylation in mice. Thus, our findings suggest that PM_2.5-induced glycolysis and subsequent modification of histone lactylation play critical role in the PM_2.5-associated pulmonary fibrosis.

Keywords: Epithelial-mesenchymal transition; Glycolysis; Histone lactylation; Macrophage; PM(2.5).