RORalpha mediates chronic subretinal inflammation associated with AMD

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.

Grant Number: 5R01EY024963-09
NIH Institute/Center: NIH
Principal Investigator: JING CHEN