Bacterial infection triggers a cytokine storm that needs to be resolved to maintain the host’s wellbeing. Here, we report that ablation of m⁶A methyltransferase subunit METTL14 in myeloid cells exacerbates macrophage responses to acute bacterial infection in mice, leading to high mortality due to sustained production of pro-inflammatory cytokines. METTL14 depletion blunts Socs1 m⁶A methylation and reduces YTHDF1 binding to the m⁶A sites, which diminishes SOCS1 induction leading to the overactivation of TLR4/NF-κB signaling. Forced expression of SOCS1 in macrophages depleted of METTL14 or YTHDF1 rescues the hyper-responsive phenotype of these macrophages in vitro and in vivo. We further show that LPS treatment induces Socs1 m⁶A methylation and sustains SOCS1 induction by promoting Fto mRNA degradation, and forced FTO expression in macrophages mimics the phenotype of METTL14-depleted macrophages. We conclude that m⁶A methylation-mediated SOCS1 induction is required to maintain the negative feedback control of macrophage activation in response to bacterial infection.

细菌感染会引发细胞因子风暴，需要加以解决以维持宿主的健康。在这里，我们报告了骨髓细胞中 m ⁶ A 甲基转移酶亚基 METTL14 的消融加剧了巨噬细胞对小鼠急性细菌感染的反应，由于促炎细胞因子的持续产生而导致高死亡率。METTL14 消耗减弱了 Socs1 m ⁶ A 甲基化并减少了 YTHDF1 与 m ⁶ A 位点的结合，从而减少了 SOCS1 诱导，导致 TLR4/NF-κB 信号传导过度激活。SOCS1 在耗尽 METTL14 或 YTHDF1 的巨噬细胞中的强制表达在体外和体内挽救了这些巨噬细胞的高反应性表型. 我们进一步表明，LPS 处理通过促进Fto mRNA 降解来诱导Socs1 m ⁶ A 甲基化并维持 SOCS1 诱导，并且巨噬细胞中的强制 FTO 表达模拟了 METTL14 耗尽的巨噬细胞的表型。我们得出结论，需要 m ⁶ A 甲基化介导的 SOCS1 诱导来维持响应细菌感染的巨噬细胞活化的负反馈控制。