METTL1-mediated m <sup>7</sup> G methylation of <i>Sarm1</i> mRNA promotes macrophage inflammatory responses and multiple organ injury
Chao Hou, Xinru Zhang, Jie Wei, Jia-nan Wang, Jian Gao, Z.-X. Wang, Shuai-shuai Xie, Tong Chen, Tao Sun, Tian Pu, Ju-tao Yu, Xiao-Guo Suo, Zi-ye Mei, Fanrong Zhang, Juan Jin, Wenman Zhao, Yuxian Shen, Xiao‐Ming Meng
Abstract
RNA modifications regulate phenotype and function of macrophages by regulating RNA translation, splicing, and stability. However, the role of N 7 -methylguanosine (m 7 G) modification in macrophages and inflammation remains unexplored. In this study, we observed elevated levels of the methyltransferase METTL1 and m 7 G 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 m 7 G 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 m 7 G 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.