Comparative analysis of activation of macrophages/microglia in diabetic retinopathy and Familial Exudative Vitreoretinopathy

Familial Exudative Vitreoretinopathy (FEVR) and Diabetic Retinopathy (DR) are two prominent retinal diseases. The role of macrophages/microglia in the vascular dynamics of FEVR and DR is unknown and thus addressed in this study. FZD4 knockout mouse, a model for FEVR in human characterized by genetic mutations affecting angiogenesis, exhibited reduced b-wave amplitudes and decreased vascular density, replicating human FEVR symptoms. Conversely, STZ-treated C57/BL6 mouse developed heightened fasting glucose levels, reduced insulin content, and increased retinal vasculature, aligning with DR features. Further analysis revealed significant differences in macrophage/microglia populations between the two diseases. In DR, a marked increase in both number and M2-like polarization of retinal macrophages/microglia was observed, contrasting with FEVR. Moreover, DR induced substantial proinflammatory differentiation of macrophages/microglia, evidenced by elevated cytokines such as IL-1β, TNF-α, and IFNɣ. Both conditions significantly upregulated Ang-1 and IL-10, with a more pronounced IL-10 increase in DR, suggesting a more active role in tissue and vessel remodeling. Notably, DR induced higher levels of anti-inflammatory factors like bFGF, TIMP-1, TGFβ1, and VEGF-A compared to FEVR, suggesting a balance of inflammation initiation, progression and resolution. These findings highlight the distinct roles of macrophages/microglia in FEVR and DR, providing insights into their contributions to disease pathogenesis and potential therapeutic strategies through reprogramming macrophages/microglia.