Abstract
Purpose :
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, exert neuroprotective roles in the retina. Our main goal is to elucidate the role of fibrinogen in CX3CR1-mediated inflammation during DR. We hypothesize that aberrant CX3CR1 signaling and fibrinogen-mediated microglial activation leads to inflammation and neuronal loss, followed by blood-retinal barrier damage, which can be ameliorated by reducing fibrinogen levels. We also hypothesize that DR pathology in human retinas mirrors observations from mouse models.
Methods :
To analyze DR pathology hallmarks, we used a murine model of diabetes and obtained post-mortem human retinas from nondiabetic and diabetic patients. To characterize retinal pathology, microglial number and morphology, vascular damage, and fibrinogen extravasation were evaluated by immunohistochemistry. To determine effects of reducing fibrinogen in diabetic mice, the defibrinogenating agent ancrod was administered, after which retinal pathology and visual acuity were assessed.
Results :
Histopathological analyses revealed increased microglial activation, vascular aberrations, and fibrinogen deposition in both diabetic patients and mouse retinas. After ancrod treatment, diabetic mice appeared to improve visual acuity, with reduced retinal inflammation and extravasated fibrinogen.
Conclusions :
Our results show that pathological hallmarks observed in diabetic human retinas are corroborated in retinas from experimental diabetic models and that CX3CR1 signaling plays a key role in mediating neuroprotection in DR. Furthermore, ancrod administration to diabetic mice appears to dampen inflammation and vascular damage, with improvement in visual acuity. Together, these findings suggest that fibrinogen can be uniquely targeted as a novel therapeutic strategy for diabetic patients.
This is a 2021 ARVO Annual Meeting abstract.