ALKBH5-mediated m 6A RNA demethylation promotes antibacterial innate defense by intrinsically driving neutrophil generation and recruitment

Abstract Neutrophil generation and effective recruitment into the site of infection are essential for innate immune defense against bacterial infection. These processes that directed by extracellular signals such as growth factors or chemokines have been extensively studied, yet intrinsic new mechanism determining neutrophil needs further investigation. N6-methyladenosine (m 6A) RNA modification its demethylase alkB homolog 5 (ALKBH5) key epigenetic regulators immunity inflammation, whereas their role in remains unclear. Here, using cecal ligation puncture-induced sepsis to model systemic infection, we found ALKBH5 is required antibacterial intrinsically inducing recruitment. Indeed, Alkbh5-deficient mice exhibited increased mortality, higher burden proinflammatory cytokine production than wild-type littermates undergoing sepsis. Meanwhile, depletion significantly impaired immature neutrophils bone marrow also reduced infected mice. Mechanistically, imprinted generation- recruitment-promoting transcriptome signatures both mouse human during specially modulated protein expression SOCS3 CXCR2 through altering m 6A methylation-mediated decay mRNAs. Together, our findings reveal a previously unknown driving recruitment, indicating potential target controlling infections. Supported grants from National Natural Science Foundation China (81788101, 82071793), Chinese Academy Medical Sciences Innovation Fund (2021-I2M-1-017), Beijing (7212069), Nova Program (20220484065).