METTL1-mediated m7G methylation of Sarm1 mRNA promotes macrophage inflammatory responses and multiple organ injury

Abstract

RNA modifications regulate phenotype and function of macrophages by regulating RNA translation, splicing, and stability. However, the role of N⁷-methylguanosine (m⁷G) modification in macrophages and inflammation remains unexplored. In this study, we observed elevated levels of the methyltransferase METTL1 and m⁷G modifications in macrophages from mouse and human tissues during acute kidney injury (AKI). METTL1 deficiency in myeloid cells mitigated multiorgan inflammation induced by cecal ligation and puncture and renal ischemia/reperfusion. Genetic deletion of METTL1 inhibited macrophage proinflammatory responses. We identified internal Sarm1 messenger RNA (mRNA) as a target of m⁷G modification that controls macrophage metabolic reprogramming. METTL1 deficiency in macrophages inhibited metabolic reprogramming, which was reversed by SARM1 overexpression that induced NAD⁺ decline. Pharmacologically, SA91-0178, a specific METTL1 inhibitor, effectively alleviated tissue injury during septic inflammation. Collectively, our findings suggest that m⁷G modification enhances the stability of Sarm1 mRNA, thereby resulting in NAD⁺ imbalance in macrophages, indicating that METTL1 may serve as a potential therapeutic target for systemic inflammation.