Superoxide-deficient macrophages exhibit an M2 phenotype to prevent autoimmune diabetes. (BA12P.105)

Type 1 diabetes (T1D) is an autoimmune disease culminating in β-cell destruction by inducing reactive oxygen species (ROS), pro-inflammatory cytokines, and islet-infiltrating leukocytes. We recently demonstrated the importance of NADPH oxidase (NOX)-derived ROS synthesis in T1D, as Non-Obese Diabetic (NOD) mice unable to generate superoxide (NOD.Ncf1m1J) were highly T1D resistant. Therefore, we hypothesized that dampened ROS synthesis within NOD.Ncf1m1J mice contributes to blunted pro-inflammatory M1 and/or enhanced anti-inflammatory M2 macrophage responses. During spontaneous T1D progression, islet-resident NOD.Ncf1m1J macrophages exhibited an enhanced M2 phenotype in contrast to age-matched NOD with a significant (p < 0.01) increase in M2 macrophage transcripts (Ccl17, Retnla, Cd206, Arg1), and a significant (p < 0.01) decrease in M1 transcripts (Cxcl10, Ccl5, Nos2, and Tnfa). To confirm that redox status influenced macrophage differentiation, pre-activated diabetogenic BDC-2.5 CD4 T cells, which recruit pro-inflammatory M1 macrophages to destroy β-cells, were transferred into NOD.Rag.Ncf1m1J recipients possessing superoxide-deficient antigen presenting cells. We observed a decrease in IL-1β-expressing, islet-infiltrating M1 macrophages and enhanced Arginase-1-expressing M2 macrophages compared to NOD.Rag. Our results demonstrate the importance of ROS in M1 macrophage differentiation; thus, targeting macrophage redox status may represent a promising therapy in halting T1D.