RORalpha mediates chronic subretinal inflammation associated with AMD

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Project Summary Age-related macular degeneration (AMD) is a major cause of blindness in the elderly, associated with altered lipid (cholesterol) metabolism and altered immunity (complement). Chronic subretinal inflammation occurs during aging in clinical and experimental AMD, and is associated many other neurodegenerative diseases. Resolving harmful persistent inflammation is important to protect the retinas from age-related damage. Previous work identified that retinoic-acid-receptor-related orphan receptor alpha (RORαa lipid (cholesterol)-sensing nuclear receptor, is genetically linked with the risk for wet AMD. RORαis a transcription factor that regulates lipid homeostasis and inflammation, both important for AMD. Our preliminary results from mouse models of aging and retinal degeneration indicate that: 1) RORα deficiency induces subretinal deposits, accumulation of lipid- enriched microglia/macrophages in the subretinal space in aging mice; 2) RORα deficiency worsens light- induced retinal degeneration; 3) Loss of RORα induces microglia/macrophage lipogenesis and chronic inflammation in RPE/choroid with induction of PPARγ, a key lipid metabolic regulator; 4) RORα deficiency alters complement factors and suppresses complement inhibitory factor H (CFH, one of the strongest AMD susceptibility genes) in the liver and in the eyes; and 5) RORα directly regulates both CFH and PPARγ transcription. Based on these findings, we hypothesize that during aging, RORα links lipid dysregulation with subretinal microglia/macrophage lipogenesis and complement alteration, to suppress chronic pathogenic subretinal inflammation; RORα activation may resolve chronic inflammation associated with early AMD. We will test this hypothesis with three aims. Aim I: To determine whether RORα deficiency exacerbates pathological subretinal inflammation and retinal degeneration in RORα deficient mice during aging and with a light-induced retinal degeneration model. Aim II: To assess if RORα deficiency induces chronic subretinal inflammation by accelerating microglia/macrophage recruitment, lipogenesis, and function through PPARγ, and/or by controlling systemic and/or local CFH function and complement cascade. Aim III: to determine if RORα activation resolves chronic inflammation and protects the retinas in chronic dry AMD models and in light-induced retinal degeneration model. This work will uncover the potential role of RORα as a key mediator of lipid homeostasis and altered innate immunity in chronic subretinal inflammation associated with AMD, and develop potential new treatments via activating RORα to resolve persistent inflammation during aging and protect retinas.