Enhanced M2 Polarization of Retinal Microglia in Streptozotocin-Induced Diabetic Mice upon Autoimmune Stimulation

Background: This study aimed to investigate the impact of the diabetic environment on the development of experimental autoimmune uveoretinitis (EAU) and the activation status of microglia in the eye. Methods: EAU was induced in wild-type (WT) and streptozotocin (STZ)-induced diabetic mice (STZ-EAU mice). Disease severity was assessed using funduscopy, optical coherence tomography (OCT), and histopathological analysis. The proportions of Th1, Th17, and regulatory T cells in the spleen were analyzed by flow cytometry. Retinal microglia were quantified using immunohistochemistry. To further characterize retinal cell populations and gene expression profiles, single-cell RNA sequencing (scRNA-seq) was performed. Results: STZ-EAU mice exhibited significant reductions in both the incidence and severity of EAU compared with WT-EAU mice. These were accompanied by a decreased proportion of Th1 cells, which are crucial for EAU pathogenesis, in the spleens of STZ-EAU mice. Retinal microglial accumulation was markedly reduced in STZ-EAU mice compared with WT-EAU mice. scRNA-seq analysis revealed a significant change in the microglial phenotype in STZ-EAU mice, characterized by decreased expression of MHC class I/II and the suppression of antigen presentation signaling pathways. Activated microglia in STZ-EAU mice showed reduced gene expression of M1 markers (CD68, CD74, and IL1B) and increased gene expression of M2 markers (MSR1, CD163, and MRC1), suggesting a shift toward an anti-inflammatory M2 phenotype. Conclusions: EAU is suppressed in STZ-induced diabetic mice, likely due to alterations in microglial polarization toward an M2 phenotype. These results suggest a decrease in T cell responses to pathogens in a diabetic environment, which could be one of the underlying factors for the increased susceptibility to infection in diabetic patients. Inhibiting the M2 polarization of microglia may reduce the susceptibility to infection in patients with diabetes.