Map4k1缺失对DSS诱导的小鼠结肠炎的保护作用OA

Objective:To explore the role of mitogen-activated protein kinase kinase kinase kinase 1(MAP4K1)in the development of colitis in mice and its mechanism of action.Methods:The expression of MAP4K1 in the intestinal tissue of inflammatory bowel disease(IBD)patients was analyzed through the GEO database.An experimental colitis model was induced by 3%dextran sulfate sodium salt(DSS).HE staining and RT-qPCR were used to verify the role of MAP4K1 in inflammation and tissue damage.Flow cytometry and immunohistochemistry were used to analyze the effect of MAP4K1 on intestinal epithelial barrier function and cell apoptosis/necrosis,and its role in immune cell infiltration.The regulatory role of MAP4K1 on epithelial cell integrity and apoptosis,and its relationship with the p53 signaling pathway were also studied.Results:Analysis of the GEO database showed that the expression level of Map4k1 mRNA in the intestine of IBD patients was up-regulated compared with that of normal people.Animal experiments indicated that,in comparison with wild-type(WT)mice,Map4k1-/-mice exhibited alleviated colitis symptoms in the DSS-induced experimental colitis model,which were specifically characterized by slowed weight loss,reduced colon length shortening,attenuated histopathological damage,significantly decreased mRNA expression levels of inflammation-related cytokine genes(including Il6,Tnf,Kc,and Mcp-1)in mice.additionally,phosphorylation of IκB was inhibited.Mechanistic studies found that the absence of Map4k1 enhanced intestinal epithelial integrity and increased the mRNA and protein expression levels of barrier-related molecules(Muc2,E-cadherin,etc.).After DSS treatment,the infiltration and activation levels of intestinal immune cells[macrophages(MACs),dendritic cells(DCs)and polymorphonuclear leukocytes(PMNs)]were similar between WT and Map4k1-/-mice.However,the ratio of the anti-apoptotic protein Bcl-2 to the pro-apoptotic protein Bax was significantly increased in Map4k1-/-mice compared to WT mice.Similarly,overexpression of Map4k1 led to increased epithelial cell apoptosis.Further research indicated that Map4k1 deficiency could suppress the expression of p53.Conclusion:MAP4K1 is upregulated in IBD patients.Its deficiency alleviates IBD symptoms,possibly promoting colitis development by activating p53 to induce apoptosis of intestinal epithelial cells.