ALKBH5 mediates silica particles-induced pulmonary inflammation through increased m6A modification of Slamf7 and autophagy dysfunction

Silica particles are commonly encountered in natural and industrial activities. Long-term environmental exposure to silica can result in silicosis, which is characterized by chronic inflammation and abnormal tissue repair in lung. To uncover the role of m6A modification in silica-induced pulmonary inflammation, we conducted this study using established mouse and macrophage models. In this study, the aerodynamic diameter of silica particles was approximately 1~2 μm. We demonstrated that silica exposure in mice caused pulmonary inflammation and increased global m6A modification levels, the downregulation of alkB homolog 5 (ALKBH5) might contribute to this alteration. Besides, we found that F4/80, a macrophage-specific biomarker, was co-expressed with ALKBH5 through dual immunofluorescent staining. In vitro studies using MeRIP assays suggested that Slamf7 was a target gene regulated by m6A modification, and specific inhibition of ALKBH5 increased Slamf7 expression. Mechanistically, ALKBH5 promoted m6A modification of Slamf7, which decreased Slamf7 mRNA stability in an m6A-dependent manner, ultimately regulating Slamf7 expression. In addition, silica exposure activated PI3K/AKT and induced macrophage autophagy. Inhibition of Slamf7 promoted autophagy, reduced the secretion of pro-inflammatory cytokines, and improved silica-induced pulmonary inflammation. In summary, ALKBH5 can regulate silica-induced pulmonary inflammation by modulating Slamf7 m6A modification and affecting the function of macrophage autophagy.