Role of Fractalkine and CX3CR1 Polymorphic Variants in Microglia Function in Diabetic Retinopathy

Diabetic retinopathy (DR), an incurable eye disease caused by prolonged high glucose levels in the retina, damage retinal blood vessels leading to hemorrhages, ischemia and ultimately vision loss. DR is diagnosed once vascular damage in the retina has reached detectable levels and the available treatments only slow vascular damage but do not fully halt or reverse the injury or restore vision loss. Microglia, the resident immune cells of the central nervous system (CNS), become activated due to hyperglycemia and are believed to contribute to the development of DR. CX3CR1, a receptor constitutively expressed by microglia in the CNS, and its ligand, fractalkine (FKN), a chemokine expressed uniquely in neurons, are critical components regulating microglial activation with FKN serving as a dampening signal for microglia-mediated inflammation. A polymorphic variant of the CX3CR1 gene, present in 25% of the population, causes the CX3CR1 receptor to be defective in adhesion to FKN, and individuals harboring this variant are at greater susceptibility to developing DR. We do not understand how disease is initiated and what is the contribution of microglia to inflammatory mediated damage in the diabetic retina. Therefore, I will deplete microglia to determine if downregulating microglia mediated inflammation will serve clinically relevant to prevent neuronal and vascular damage and hence vision loss.