Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation

Ye Sun, Chi Hsiu Liu, John Paul SanGiovanni, Lucy P. Evans, Katherine T. Tian, Bing Zhang, Andreas Stahl, William T. Pu, Theodore M. Kamenecka, Laura A. Solt, Jing Chen

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Pathologic ocular angiogenesis is a leading cause of blindness, influenced by both dysregulated lipid metabolism and inflammation. Retinoic-acid-receptor-related orphan receptor alpha (RORα) is a lipid-sensing nuclear receptor with diverse biologic function including regulation of lipid metabolism and inflammation; however, its role in pathologic retinal angiogenesis remains poorly understood. Using a mouse model of oxygen-induced proliferative retinopathy, we showed that RORα expression was significantly increased and genetic deficiency of RORα substantially suppressed pathologic retinal neovascularization. Loss of RORα led to decreased levels of proinflammatory cytokines and increased levels of antiinflammatory cytokines in retinopathy. RORα directly suppressed the gene transcription of suppressors of cytokine signaling 3 (SOCS3), a critical negative regulator of inflammation. Inhibition of SOCS3 abolished the antiinflammatory and vasoprotective effects of RORα deficiency in vitro and in vivo. Moreover, treatment with a RORα inverse agonist SR1001 effectively protected against pathologic neovascularization in both oxygen-induced retinopathy and another angiogenic model of very-low-density lipoprotein receptor (Vldlr)-deficient (Vldlr-/-) mice with spontaneous subretinal neovascularization, whereas a RORα agonist worsened oxygen-induced retinopathy. Our data demonstrate that RORα is a novel regulator of pathologic retinal neovascularization, and RORα inhibition may represent a new way to treat ocular neovascularization.

Original languageEnglish (US)
Pages (from-to)10401-10406
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number33
DOIs
StatePublished - Aug 18 2015
Externally publishedYes

Keywords

  • Inflammation
  • Neovascularization
  • Retinopathy
  • Rorα
  • SOCS3

ASJC Scopus subject areas

  • General

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