Abstract
Visual function depends on the intimate structural, functional and metabolic interactions between the retinal pigment epithelium (RPE) and the neural retina. The daily phagocytosis of the photoreceptor outer segment tips by the overlaying RPE provides essential nutrients for the RPE itself and photoreceptors through intricate metabolic synergy. Age-related retinal changes are often characterized by metabolic dysregulation contributing to increased lipid accumulation and peroxidation as well as the release of proinflammatory cytokines. LGM2605 is a synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant and anti-inflammatory properties demonstrated in diverse in vitro and in vivo inflammatory disease models. In these studies, we tested the hypothesis that LGM2605 may be an attractive small-scale therapeutic that protects RPE against inflammation and restores its metabolic capacity under lipid overload. Using an in vitro model in which loss of the autophagy protein, LC3B, results in defective phagosome degradation and metabolic dysregulation, we show that lipid overload results in increased gasdermin cleavage, IL-1 β release, lipid accumulation and decreased oxidative capacity. The addition of LGM2605 resulted in enhanced mitochondrial capacity, decreased lipid accumulation and amelioration of IL-1 β release in a model of defective lipid homeostasis. Collectively, these studies suggest that lipid overload decreases mitochondrial function and increases the inflammatory response, with LGM2605 acting as a protective agent.
Highlights
By day 7, IL-1β release was 5- fold higher in retinal pigment epithelium (RPE)-LC3B cells as compared to controls (Figure 1E)
We focused on defining the relationship between defective phagosome clearance and loss of lipid homeostasis resulting in oxidative stress and cytokine release by the RPE
We further evaluated the potential for LGM2605, a synthetic lignin with potent antioxidant and mito-protective properties, to restore RPE lipid homeostasis and ameliorate cytokine release
Summary
In the aging human eye, oxidative damage, metabolic dysregulation and accumulation of pro-oxidant compounds cause the functional decline of the RPE, which contributes to age-related macular degeneration (AMD) [1,2,3]. AMD is a late-onset, progressive disease that generally affects individuals over the age of 60 [4]. It is the major cause of vision loss in the elderly, affecting over 2 million people in the US. Uncompensated oxidative stress is a major contributor to RPE dysfunction and cell injury, and in AMD is a known risk factor in disease progression. In animal models of chronic oxidative stress, the retina and RPE develop pathologic lesions characteristic of early AMD [6,7]. Undegraded lipids serve as substrates for peroxidation reactions in this oxidative environment [9,10]
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