P0099 Histone H4 lysine 12 lactylation in CD4+ T cells promotes the progression of Ulcerative Colitis through PKM2/glycolysis loop and PKM2/STAT3 signaling pathway

Abstract Background Immune dysfunction- the imbalance of Th17/Treg ratio is the main pathogenic factor of ulcerative colitis (UC). Histone lactylation is a new protein modification and could regulate immune function. However, the roles of histone lactylation in the naïve CD4+ T cell differentiation and UC progression remain unclear. Methods We employed a mouse model to elucidate the mechanism by which lactic acid facilitates the progression of ulcerative colitis through the inhibition of PKM2 and targeted knockout of Pkm2 in CD4+ T cells. Results Our study shows a high level of H4K12la in CD4+ T cells at the intestinal inflammatory sites in UC, which is specifically enriched at the promoters of glycolytic genes including pyruvate kinase 2 (PKM2). Then PKM2 can activate the transcriptional activation protein 3 (STAT3) signaling pathway, thereby inducing the differentiation of naïve CD4+ T cells into Th17 cells and inhibiting Treg cell differentiation, and cause sustained release of pro-inflammatory cytokines, which finally exacerbates intestinal inflammation. In addition, as a key glycolysis enzyme, the upregulation of PKM2 expression could accelerate more lactate production in a positive feedback way. Both pharmacologic inhibition of PKM2 and CD4+ T cell-specific ablation of Pkm2 could block lactate production and then downregulate the ratio of Th17/Treg to alleviate colitis. Conclusion The study demonstrate the pro-inflammatory role of H4K12la in CD4+ T cells, and PKM2 may be a potential target for the treatment of UC.