Nlrp3 inflammasome activation in early diabetic retinopathy

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Abstract/Summary Hallmark pathologic processes of diabetic retinopathy (DR) include neural and glial dysfunction, recruitment of inflammatory cells, endothelial dysfunction, vascular occlusion, and loss of the blood retinal barrier. Inflammasomes are innate immune signaling platforms implicated in acute responses to foreign pathogens as well as numerous chronic neurodegenerative- and inflammatory-related diseases. Inflammasome blockade is being explored for multiple complex neurovascular conditions including Alzheimer's disease, atherosclerosis, age-related macular degeneration, and rheumatoid arthritis. Clinical and preclinical evidence suggest that inflammasome activity may also contribute to pathological hallmarks of DR by promoting production of inflammatory cytokines, leukostasis, and loss of microvascular integrity. Despite this evidence, major gaps in knowledge persist with respect to the timing, cellular sources, and pathological implications of inflammasome activation in the context of diabetic retinopathy. The overall hypothesis of this proposal is that NLRP3 inflammasome activation in circulating immune cells and resident neuroglia drives neuronal and microvascular dysfunction in diabetic retinopathy. We will test this hypothesis in three specific aims: 1) We seek to identify cell types that exhibit inflammasome activation and the timing thereof in an animal model of type 1 diabetes; 2) We seek to determine the contribution of core inflammasome constituents to hallmark pathological phenotypes in animal models of retinal pathologies due to diabetes. To accomplish this, we will utilize global and cell-specific genetic knockouts of inflammasome constituents in models of diabetes; 3) We seek to test the efficacy of pharmacological inflammasome inhibitors in preclinical models of neural, immune, and vascular defects due to diabetes. Collectively, these thematically related, but independent aims will establish the contribution of inflammasome in pathological processes of diabetes in the retina. These studies may thereby open new interventional avenues for this prevalent blinding condition.