The Role And Mechanism Of Tnfaip2 On DSS Induced Colitis

Inflammatory bowel disease(IBD),including Crohn’s disease(CD)and ulcerative colitis(UC),is a group of chronic intestinal inflammatory diseases of unknown cause,characterized by recurrent diarrhea,abdominal pain,mucous and bloody stools.The incidence of IBD is increasing year by year and has become a common digestive system disease in China.Chronic prolongation of IBD is difficult to cure,and it is easy to develop into colon cancer,which is a serious threat to human life and health.The etiology of inflammatory bowel disease is complex,with infection,heredity,environment,and immune dysfunction as the main causes,but the specific pathogenesis is still unclear.The intestinal tract is the main site of nutrient absorption and an important metabolic and immune organ.It has a unique regional immune system,which is composed of three parts of intestinal lymphoid tissue,namely,intraepithelial lymphocytes,intestinal mucosa lamina propria,and small intestinal mucosa and submucosal lymphoid tissue,in which there are a large number of T cells and antibody-forming cells(plasma cells).It can secrete a variety of cytokines,and secreted immunoglobulin plays an important role in maintaining intestinal immune surveillance,eliminating pathogens and preventing pathogen invasion.TNF-α is a pro-inflammatory cytokine,and the dysregulation of its synthesis is associated with human autoimmune diseases and tumorigenesis.Tumor necrosis factor alpha induced protein2(Tnfaip2)is the main response gene to TNF-α.Tnfaip2 is not only a multifunctional mediator of inflammation,angiogenesis,and tunnel nanotube formation but also a regulatory factor of cell proliferation and migration,playing an important role in a variety of tumor and infectious diseases.At present,there is only one report on the increased expression of Tnfaip2 in DSSinduced colon inflammation,but the specific mechanism studies are lacking,especially on whether Tnfaip2 can regulate the unique immune function of the intestine and play a role in DSS-related colitis.Therefore,this paper takes the regional immune characteristics of the intestine as the entry point to explore the role and mechanism of Tnfaip2 in DSS-related colitis.In this study,a mouse colitis model was established by DSS.The results showed that the inflammatory response was more serious in Tnfaip2-/-mice compared to C57 controls.We found more obvious colon shortening,faster weight loss,higher disease activity index score,and more serious damage of mucosal gland structure in Tnfaip2-/-mice treated with DSS.In addition,the serum pro-inflammatory factor levels of Tnfaip2-/-mice were significantly higher than that of WT controls,while the anti-inflammatory factor level was lower.The results of flow cytometry analysis of immune cells in peripheral blood and colon tissues of mice showed that the number of Tregs and CD8αα+T cells was significantly reduced in the Tnfaip2-deficient mice models compared with the control mice,while the levels of inflammatory macrophages and neutrophils were significantly increased.Moreover,a higher level of Myeloid-derived suppressor cells(MDSCs)could be detected in the intestinal tissues of model mice with the deletion of Tnfaip2 gene.In vitro induction of MDSCs showed that Tnfaip2 gene deletion could promote the myeloid progenitor cells to differentiate into MDSCs.These results suggest that the deletion of Tnfaip2 gene is more likely to induce DSS-related colitis,which is related to the decrease of inhibitory lymphocytes in intestinal immunity and the increase of inflammatory immune cells.Very interestingly,and the MDSC is more easy to be accumulated and activated at the inflammatory site to enhance inflammatory stimulation and promote the inflammatory response.