The Role of Fibrinogen in CX3CR1-Mediated Inflammation in the Diabetic Retina
Microglia-mediated inflammation plays a significant role in neuronal and vascular damage in diabetic retinopathy (DR), but the mechanism linking inflammation, neurodegeneration, and impaired vascular integrity is still unclear. Our previous studies from diabetic mouse models exhibiting systemic inflammation showed that fractalkine (FKN), a neuronal-derived chemokine, and its microglial receptor, CX3CR1, are neuroprotective in the retina. This dissertation aims to elucidate the role of fibrinogen in CX3CR1-mediated inflammation during DR and test the hypothesis that fibrinogen-mediated microglial activation leads to inflammation, blood-retinal barrier damage, and vision loss, which can be ameliorated by reducing fibrinogen levels. To explore 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. To characterize DR pathology hallmarks, including gliosis, vascular integrity, and fibrinogen deposition, murine and post-mortem human retinas were analyzed by immunohistochemistry. Histopathological analyses revealed increased microglial activation, vascular aberrations, and fibrinogen deposition in both diabetic mouse and human retinas. Notably, after treatment with ancrod, diabetic mice appeared to improve visual acuity, which was associated with reduced retinal inflammation and less extravasated fibrinogen. Finally, pathological hallmarks of gliosis and vascular aberrations characterized in our inflammatory diabetic animal model are consistent with those in diabetic human retinas, in which evidence of an inflammatory microenvironment, with microgliosis and impaired vasculature, was observed. Overall, these findings suggest that CX3CR1 signaling plays a key role in mediating neuroprotection in DR and posit that fibrinogen can be uniquely targeted as a novel therapeutic strategy to reduce inflammation-mediated vision deficits in diabetic patients.