ROR alpha is crucial for attenuated inflammatory response to maintain intestinal homeostasis

Abstract

Retinoic acid-related orphan receptor alpha (ROR alpha) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific ROR alpha-deficient (ROR alpha(Delta I)(EC)) mice and find that ROR alpha is crucial for maintaining intestinal homeostasis by attenuating nuclear factor kappa B (NF-kappa B) transcriptional activity. ROR alpha(Delta I)(EC) mice exhibit excessive intestinal inflammation and highly activated inflammatory responses in the dextran sulfate sodium (DSS) mouse colitis model. Transcriptome analysis reveals that deletion of ROR alpha leads to up-regulation of NF-kappa B target genes in IECs. Chromatin immunoprecipitation analysis reveals corecruitment of ROR alpha and histone deacetylase 3 (HDAC3) on NF-kappa B target promoters and subsequent dismissal of CREB binding protein (CBP) and bromodomaincontaining protein 4 (BRD4) for transcriptional repression. Together, we demonstrate that ROR alpha/HDAC3-mediated attenuation of NF-kappa B signaling controls the balance of inflammatory responses, and therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of chronic inflammatory diseases, including inflammatory bowel disease (IBD).