Myeloid deficiency of RORα exacerbates lipid dysregulation and laser-induced choroidal neovascularization

Dysregulated lipid and cholesterol metabolism is implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of vision loss. Retinoic acid receptor-related orphan receptor alpha (RORα) is a lipid-sensing nuclear receptor genetically associated with neovascular AMD. We investigated the role of RORα in regulating AMD-like pathologies and laser-induced choroidal neovascularization (CNV) through mediating myeloid cell lipid homeostasis and function. Both systemic (Rora^sg/sg) and myeloid-specific (Rora^fl/fl;LysMCre) RORα deficient mice exhibited fundus lesions with aging, and exacerbated CNV with chronic subretinal inflammation, with subretinal accumulation of lipid-laden activated microglia/macrophages, and increased levels of pro-inflammatory cytokines. RORα-deficient macrophages showed enhanced lipid droplet formation and upregulation of peroxisome proliferator-activated receptor gamma (PPARγ), a lipogenic RORα target gene. Pharmacological inhibition of RORα in cultured macrophage recapitulated the effects of RORα deficiency on lipid enrichment and inflammation, whereas PPARγ inhibition in RORα deficient mice partially reversed the effects on laser-induced CNV, lipid accumulation and inflammation. Additionally, migratory chemokine receptors, including CX3CR1 and CD47, were downregulated in RORα-deficient myeloid cells, contributing to impaired elimination of inflammatory cells from the subretinal space. These findings identify RORα as a critical transcriptional regulator that links lipid dysregulation to persistent subretinal inflammation and pathological CNV highly relevant in AMD.