The Role Of FAM114A1 In The Development Of Dextran Sodium Sulfate-induced Ulcerative Colitis

Ulcerative colitis(UC)is a recurrent intestinal inflammatory reaction,but the pathogenesis mechanism under the disease is not clear.It is generally accepted that genetic and environmental factors,as well as the immune dysfunction contribute to the disease.Due to the multiple causal factors,UC is hard to cure in clinical treatment.Therefore,it is very important and necessary to find new targets,which can provide more information for drug development and clinical treatment.Fam114a1 protein was first discovered and identified in the nervous system and plays a role in the development of nerve cells.Some relevant studies suggest that Fam114al may also play a role in UC development.In this study,the role of Fam114al in the colitis and the molecular mechanism under the disease were explored through a mouse colitis model induced with DSS.The expression of genes during the occurrence of colitis in mice was analyzed through the published data firstly and found that the expression of Fam114a1 decreased in colitis tissues.Then,DSS was used to induce colitis in wild mice,and the protein expression of Fam114al was detected.The results showed that the expression of Fam114a1 was decreased.And these results suggested that the expression of Fam114a1 decreased during the occurrence of colitis,indicated that Fam114a1 may play a role in the occurrence of colitis.Fam114a1 gene knockout mice were more sensitive to DSS-induced colitis.Fam114a1-/-mice had more severe inflammatory activity,tissue damage and increased infiltration of immune cells in the colon tissue.These results indicated that Fam114a1 has a protective effect on colitis.The Faml14a1-/-mice and Faml14a1+/+ mice were cohoused in the same cage and then treated with DSS to induce colitis.The results showed that Fam114a1-/-mice in the same cage were sensitive to colitis.The colon inflammatory reaction and tissue damage were more serious in Faml14a1-/-mice.Further,a bone marrow transplantation experiment in mice was conducted,and found that mice without Fam114al protein in immune cells were more sensitive to DSSinduced colitis,while mice without Fam 114al protein in somatic cells showed no difference in response to DSS-induced colitis.Then,the results showed that Fam114al mainly plays its role in macrophages through flow cytometry and immune cells elimination in vivo.Fam114a1 can affect the function of macrophages to protect colitis.In subsequent studies,the results showed that the absence of Fam114al protein in macrophages leads to the activation of NLRP3 inflammasome and enhanced inflammatory response.Conversely,overexpression of Fam114al protein in macrophages inhibits the activation of NLRP3 inflammasome and reduces the inflammatory response.In further studies,the results showed that there was no interaction between Faml14a1 protein and NLRP3 inflammasome,and the inhibitory effect of Fam114a1 protein on inflammasome was mainly achieved by maintaining intracellular reactive oxygen species level.Loss of Fam114al protein in macrophages would lead to imbalance of intracellular REDOX homeostasis and the elevation of ROS level.In summary,Fam114a1 probably maintain the REDOX homeostasis in macrophages and ensure the balance of intracellular ROS level,thus reducing the activation of inflammasome and inhibiting the development of colitis.Therefore,our results reveal an important role and mechanism of Fam114al in colitis and provide a new target for the treatment of colitis.