ALKBH5 deletion ameliorates inflammation by regulating IRF3 signaling in an m6A-dependent manner after myocardial infarction.

Abstract

AlkB homolog 5 (ALKBH5) plays an important role in ischemia/reperfusion (I/R), cardiac hypertrophy and other cardiovascular diseases (CVDs). However, whether ALKBH5 regulates the inflammatory response by mediating M1/M2 macrophage conversion after myocardial infarction (MI) is unclear. In this study, we found that ALKBH5 protein expression was significantly downregulated in MI mice. To investigate the role of ALKBH5 in the inflammatory response after MI, we assessed the expression of interleukin-6 (Il-6), interleukin-1β (Il-1β), tumor necrosis factor-α (Tnf-α) and interferon-Ⅰ (Ifn-Ⅰ) by qRT‒PCR and found that ALKBH5 knockout improved cardiac function, reduced pro-inflammatory cytokine release and decreased cardiomyocyte apoptosis. In addition, the knockdown of ALKBH5 significantly inhibited the release of pro-inflammatory cytokines and the migration of RAW264.7 macrophages treated with lipopolysaccharide (LPS). Mechanistically, our results suggested that ALKBH5 potentially recognized the m⁶A binding site on interferon regulatory factor 3 (IRF3) and regulated the IRF3 expression to influence macrophage M1/M2 phenotypic transition and inflammatory cytokine release. In conclusion, our results indicated that ALKBH5 ablation inhibited inflammation by regulating the transcription of IRF3. This study provides new insights into the clinical management of the inflammatory response after MI.