Role of Fractalkine Signaling in the Regulation of Microglialmediated Inflammation and Pathology during Diabetic Retinopathy

Date
2017
Authors
Mendiola, Andrew S.
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Abstract

Diabetic retinopathy (DR) is the leading cause of incurable blindness amongst working-aged adults. Clinically, DR is characterized as a vasculopathy, in which chronic (>6 months) diabetes in rodent models recapitulates capillary degeneration. However, increasing evidence suggest neuroinflammation and neuronal loss precede vascular changes and contributes early to pathology. Interestingly, tissue-resident microglia become reactive and contribute to the inflammatory reactions associated with DR. Yet, the mechanisms that govern the functional features of microglia and how these cells contribute to disease early in DR remain elusive. This dissertation sought to investigate the neuron-microglial signaling axis between fractalkine-CX3CR1 in regulating microglial physiology in the diabetic retina. Cx3cr1–/– mice are proinflammatory prone and known to exacerbate neuronal loss and microglial activation in models of neurodegeneration. However, the function of CX3CR1 signaling in DR remains unclear. Here, we show that soluble fractalkine is upregulated early in the diabetic retina and exerts neuroprotective responses in microglia. Additionally, we demonstrate that the blood-protein fibrinogen leaks into the retina by month 4 of diabetes; a phenotype we reproduced in a model of endotoxin-induced systemic inflammation in nondiabetic and diabetic Cx3cr1–/– mice. These data suggest that CX3CR1 may indirectly influence the integrity of the blood-retinal barrier during systemic inflammation, which is common in diabetic patients. Lastly, we show that mice expressing the human CX3CR1-M280 polymorphism accelerates DR pathogenesis relative to wild type mice. Together, these data suggest that enhancing CX3CR1 signaling may provide a therapeutic strategy to mitigate microglial-mediated inflammation during DR.

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Keywords
CX3CR1, Diabetic Retinopathy, fractalkine, Microglia, Neuroinflammation, Neuroprotection
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Department
Integrative Biology