Abstract
Purpose :
Diabetic retinopathy (DR), an incurable eye disease caused by prolonged high glucose levels in the retina, is a leading complication of diabetes mellitus and the leading cause of blindness amongst working age adults. Chronic hyperglycemia damages retinal blood vessels leading to hemorrhages, ischemia and ultimately vision loss. Microglia, the resident immune cells of the central nervous system, are believed to contribute to the development of DR. Microglial activation is largely regulated via the CX3CR1-fractalkine (FKN) signaling axis in which microglia express the CX3CR1 receptor, and neurons express it’s only ligand, FKN. A polymorphic variant of the CX3CR1 gene, present in 25% of the population, causes the CX3CR1 receptor to be adhesive defective to FKN. Previous studies have shown that aberrantly activated microglia in the diabetic retina are responsible for increased vascular damage, microglial clustering around vascular lesions, fibrinogen leakage, microgliosis, and up-regulation of proinflammatory mediators in CX3CR1-KO and human CX3CR1I249V/M280 expressing mice. Microglia appear to play an important role in mediating neuroretinal inflammation and degradation in DR. To understand the role of microglia in DR progression we depleted microglia to determine if strategies to downregulate microglia mediated inflammation can prevent neuronal damage and hence vision loss.
Methods :
Utilizing a genetic model using mice expressing an inducible Cre under the CX3CR1 promoter and the DTR gene under the Rosa 26 promoter (CX3CR1CreER:R26iDTR), expression of DTR by CX3CR1-expressing cells only occurs upon tamoxifen (TAM) treatment, rendering microglia susceptible to the effects of diphtheria toxin.
Results :
Following acute microglia depletion in diabetic CX3CR1CreER:R26iDTR mice, we depleted ~90% of microglia in the retina without depleting CX3CR1-expressing cells in the periphery. We observed an increase in neuronal cell loss and astrogliosis, without significant axonal damage. These results reveal that we can successfully deplete microglia in the retina without effecting peripheral immune cells or eliciting neurotoxic effects in the murine diabetic retina.
Conclusions :
Further studies looking at chronic depletion of activated microglia and aberrantly activated CX3CR1-M280 microglia in DR retinas are crucial to potentially to ameliorate inflammatory-mediated damage to neurons.
This is a 2021 ARVO Annual Meeting abstract.