Fibrinogen Depletion Ameliorates Inflammation and Vision Loss in Mouse Models of Diabetes

Abstract

Abstract Microglia-mediated inflammation plays a significant role in neuronal and vascular damage in diabetic retinopathy, but the mechanism linking inflammation, neurodegeneration, and impaired vascular integrity is still unclear. Our previous studies from diabetic mouse models showed accumulation of fibrinogen, at vessel lesions surrounded by perivascular microglial clusters. In this study, we evaluated whether the pathological hallmarks of gliosis and vascular aberrations characterized in diabetic animal models are consistent with those in diabetic human retinas. Postmortem human retinas were analyzed by immunohistochemistry for markers of gliosis, vascular integrity, and fibrinogen deposition. Immunohistochemical and gene expression analyses of human postmortem retinas revealed evidence of an inflammatory microenvironment, with microgliosis and impaired vasculature. To define the therapeutic potential of reducing fibrinogen in DR, the defibrinogenating agent ancrod was administered in a two-hit inflammatory diabetic mouse model, after which retinal pathology and visual acuity were assessed. Histopathological analyses revealed microglial activation, vascular aberrations, and fibrinogen deposition in the diabetic murine retina. Notably, after treatment with ancrod, diabetic mice appeared to improve visual acuity, which was associated with reduced microglia activation and less fibrinogen deposition in the retina. This study shows that fibrinogen-mediated microglial activation, blood-retinal barrier damage, and vision loss, can be ameliorated by reducing fibrinogen levels. Overall, these findings suggest that that fibrinogen contributes to microglia-mediated inflammation in the diabetic retina. Supported by R01 EY029913