Uhrf1-mediated Tnf-? Gene Methylation Controls The Pro-inflammatory Macrophages In Inflammatory Bowel Disease

Background:Macrophages drive the pathological process of inflammatory bowel disease?IBD?mostly by secreting pro-inflammatory cytokines such as tumor necrosis factor??Tnf-??.Recent studies have indicated association between epigenetic modifications and macrophage function,but what epigenetic mechanism regulates macrophages participating in diseases remains unknown.We investigated whether the epigenetic regulator Uhrf1 play a role in innate immunity by regulating macrophages function in the intestine.Methods:We obtained the mice with Uhrf1 deficiency in macrophages(Uhrf1^fl/flLyz2-Cre mice)and mutation of Uhrf1 DNA methylation regulatory site(Uhrf1^YP187/188AA mice),and assessed the susceptibility of two transgenic mice and wild type?WT?mice to dextran sodium sulfate?DSS?-induced colitis.We examined the cytokines derived from Uhrf1^fl/flLyz2-Cre and Uhrf1^YP187/188AA macrophages as well as WT macrophages following lipopolysaccharide?LPS?stimulation.We also analyzed the effect of pro-inflammatory cytokines on Uhrf1 expression in macrophages.Findings:Uhrf1 deficiency and Uhrf1 mutation resulted in more severe colitis undergoing DSS treatment.In vitro analysis revealed hypomethylation of Tnf-?promoter and increased Tnf-?expression in Uhrf1^fl/fll/fl Lyz2-Cre and Uhrf1^YP187/188AA macrophages following LPS activation.And anti-Tnf-?therapy implied the key role of Tnf-?to the aggravated colitis in Uhrf1 deficiency mice.Exogenous Tnf-?triggered macrophage activation through destabilizing Uhrf1 protein,driving IBD progression.Interpretation:In conclusion,we identified that Uhrf1-mediated DNA methylation controls Tnf-?expression of macrophages in the experimental colitis resembling IBD.The epigenetic mechanism of macrophage activation may provide new therapeutic approach for IBD treatment.