Abstract
We have reported that ZFP36 promotes Fto mRNA degradation to regulate N 6-adenomethylation (m6A) status in macrophages. Here we showed that Zfp36 deletion from macrophages triggered excessive systemic inflammation, whereas Fto ablation suppressed systemic inflammation in sepsis models. Consistently, Zfp36 -/- bone-marrow-derived macrophages (BMDMs) exhibited nuclear factor κB (NF-κB) overactivation and excessive cytokine induction upon lipopolysaccharide (LPS) challenge, whereas NF-κB signaling and cytokine production were suppressed in Fto -/- BMDMs. LPS failed to induce SOCS1 to a proper level in Zfp36 -/- BMDMs because Socs1 transcript was under-methylated, whereas this transcript was hyper-methylated in Fto -/- BMDMs leading to SOCS1 over-induction, indicating the ZFP36-FTO axis controls Socs1 m6A status to regulate macrophage activation. Zfp36 deletion abrogated LPS-induced Fto down-regulation, whereas Fto knockdown rescued Zfp36 -/- BMDMs from overactivation, confirming FTO acts downstream of ZFP36 to promote macrophage septic response. FTO inhibitors effectively suppressed macrophage cytokine production and curbed systemic inflammation, demonstrating FTO is a druggable target for sepsis treatment.