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Matt Rutar, Riccardo Natoli, Nilisha Fernando, Jan Provis; Obesity-induced metabolic disturbance drives complement activation by retinal microglia. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4606. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Dysregulation of complement is strongly implicated in the pathogenesis of AMD. Though microglia have been implicated in augmenting complement activation though secretion of vital complement components, the environmental factors that elicit such damaging responses are unclear. Clinical studies have recently linked obesity with increased risk of AMD, and here we seek to determine whether obesity promotes excessive complement activation by microglia via oxidative perturbation in the retinal environment.
Retinas from obese leptin deficient mice (ob/ob) were compared to age-matched wild type controls for retinal function (ERG, n=7) and gene expression analysis of retinal stress (Gfap), oxidative stress (Gpx3 and Hmox1), and complement activation (C3, C2, Cfb and Cfh) (qPCR, n=9). Oxidative stress was further assessed using a ROS/RNS assay (n=6). Retinal microglia and macrophage migration to the outer retina and complement activation were determined using immunohistochemistry for IBA1 and C3, respectively (n=9). Retinas and serum were used for metabolic analysis using QTRAP mass spectrometry (n=5). Primary cultured microglia cells were also accessed for gene changes following exposure to hydrogen peroxide (n=6).
ERG recordings showed reduced retinal function in ob/ob mice (P<0.05), and correlated with increases in oxidative stress-related genes (Gpx3 and Hmox1) and ROS/RNS (P<0.05). In conjunction, the expression of a number of metabolites was altered in ob/ob mice compared to controls, including both PUFAs and BCAAs (P<0.05). An increase in C3-expressing microglia and macrophages was detected in the outer retinas of ob/ob mice, while gene expression studies showed increases in complement activators C2 and Cfb, and a decrease in the inhibitor Cfh (P<0.05). Crucially, we were able to recapitulate this complement expression profile in primary culture microglia, by exposing them to oxidative stress (P<0.05).
Our present findings strongly suggest that obesity skews retinal microglia toward complement dysregulation through inducing prolonged oxidative stress within the retinal environment. Better understanding of the interplay between obesity and complement will inform efforts to limit its deleterious activation as we age, such as improvements to diet and exercise. In turn, this could help alleviate both the social and economic burdens of AMD.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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