Nuclear receptor RORa regulates retinal inflammation and neovascularization in retinopathy through SOCS3

Abstract

Purpose : Pathologic ocular neovascularization is a major cause of blindness, and linked with both dysregulated lipid metabolism and inflammation. Retinoic acid receptor-related orphan receptor alpha (RORa) is a lipid-sensing nuclear receptor regulating lipid metabolism and immunity in humans; genetic variations of RORa were associated with increasing risk of developing neovacular eye diseases. However the roles of RORa in influencing pathologic angiogenesis remains poorly understood.

Methods : A mouse model of oxygen-induced retinopathy (OIR) which mimics proliferative retinopathy was used. Neonatal mice were exposed to 75% O2 from postnatal day 7 to 12. RORa mRNA and protein levels were performed with OIR retinas compared with normoxic controls. Transcriptional target genes of RORa were analyzed by chromatin immunoprecipitation assay. Pathologic retinal vasoobliteration and neovascularization in OIR was quantified in RORa-deficient staggerer (Sg/Sg) and wild type (WT) mice, and WT mice treated with RORa inhibitors. Effects of modulating RORa in macrophages were analyzed in mouse RAW 264.7 cells in vitro.

Results : RORa expression was significantly increased in OIR mouse retinas, and localized in macrophages. Both genetic deficiency and pharmacologic inhibition of RORa substantially suppressed pathologic neovascularization in OIR, associated with decreased levels of pro-inflammatory cytokines and increased levels of anti-inflammatory cytokines. RORa transcriptionally controlled suppressors of cytokine signaling 3 (SOCS3), a critical negative regulator of inflammation. Suppression of SOCS3 diminished the pro-inflammatory effect of RORa in macrophages, and reverses macrophage RORa-mediated vascular growth ex vivo, and pathologic angiogenesis in vivo in retinopathy.

Conclusions : These findings demonstrate an important role of RORa in controlling retinal inflammation and pathologic neovascularization in proliferative retinopathy, through transcriptional modulation of SOCS3. RORa may represent a novel druggable target for treating retinopathy.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.