YTHDF1 mediates KLF2/VSIG4 axis to regulate Kupffer cell polarization to alleviate sepsis-induced liver injury

Abstract

The severity and prognosis of sepsis patients are directly linked to liver damage. Encouraging Kupffer cell transition from M1 to M2 can notably diminish inflammation and hepatic damage triggered by sepsis. Here, the effect of YTH domain N6-methyladenosine RNA binding protein F1 (YTHDF1) on Kupffer cell polarization in sepsis was evaluated. Histological staining of liver sections was conducted in CLP mice. Macrophage markers (M1:iNOS; M2:Arg1) and hepatocyte apoptosis were measured using flow cytometry. Western blot measured protein levels of YTHDF1, KLF2, VSIG4 and macrophage polarization markers. Interactions between YTHDF1, KLF2 and VSIG4 were explored by ChIP, RIP and dual luciferase reporter assays. We found that, in patients with sepsis-induced liver injury and LPS-stimulated macrophages, KLF2 and VSIG4 expression was reduced. KLF2 upregulation facilitated VSIG4 transcriptional regulation in Kupffer cells, promoting M2 polarization to alleviate hepatocyte injury triggered by LPS. The m6A level of KLF2 was regulated by YTHDF1, influencing KLF2 translation. YTHDF1 elevated KLF2 levels, fostering Kupffer M2 polarization to alleviate hepatocyte injury induced by LPS. YTHDF1 or KLF2 upregulation regulated Kupffer cell polarization, mitigating CLP-induced liver injury in septic mice. In conclusion, YTHDF1 reduced sepsis-induced inflammatory responses and liver damage by enhancing Kupffer cell M2 polarization through KLF2/VSIG4 pathway.