Ubc9-Mediated SUMOylation Regulates Macrophage Polarization In The Pathogenesis Of Type 1 Diabetes

Type 1 diabetes(T1D)is characterized by the selective autoimmune destruction of the islet ? cells,and macrophages play a significant role in this process.Small ubiquitin-like modification(SUMOylation)is an important posttranslational modification involved in T1 D pathogenesis,but its function in macrophages remains unexplored.We presently developed and used macrophage-specific ubiquitin conjugating enzyme E2(Ubc9)knockout(Lys M-Cre-Ubc9^fl/fl,KO)mice to address the impact of SUMOylation on macrophage function in a T1 D model.We observed that blocking Ubc9 in macrophages exacerbated multiple-low dose streptozotocin(MLD-STZ)-induced diabetes.Specifically,after STZ treatment,blood glucose levels were consistently elevated in the KO mice.The KO mice exhibited a higher diabetes incidence than WT controls(85% vs.55%,P< 0.01)along with a higher insulitis severity.The loss of Ubc9 impaired macrophage energy metabolism and attenuated macrophage M2 program,thereby enhancing T cell activation.Pancreas-resident macrophages,rather than migrant macrophages,played a predominant role in MLD-STZ-induced diabetes.Mechanistically,Ubc9-mediated SUMOylation of interferon regulator factor 4(IRF4)enhanced its nuclear localization and stability,thereby transcribing IL-4 and arginase 1(Arg1)to promote the macrophage M2 program.Ubc9-mediated SUMOylation modulates T1 D risk at least in part by regulating macrophage function.Modulation of disturbed SUMOylation process in macrophages,either through cell adoptive transfer or targeted drug-delivery,could help to establish a tolerant pancreatic microenvironment and promote inflammation resolution in early insulitis stage,thus hindering T1 D progression.