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RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis
Edited by David D. Moore, Baylor College of Medicine, Houston, TX, and approved September 12, 2019 (received for review May 3, 2019)

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Significance
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, and the worldwide prevalence of IBD rapidly continues to rise. It has been widely accepted that genetic predisposition remains an important risk factor of IBD in addition to microbiota, dietary environment, and immune response. In this study, we demonstrated that retinoic acid-related orphan receptor α (RORα) controls the inflammatory signaling network to maintain homeostasis in vivo in intestinal epithelium. Our study strongly proposes that RORα is a therapeutic target for the treatment of IBD.
Abstract
Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific RORα-deficient (RORαΔIEC) mice and find that RORα is crucial for maintaining intestinal homeostasis by attenuating nuclear factor κB (NF-κB) transcriptional activity. RORαΔIEC 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 RORα leads to up-regulation of NF-κB target genes in IECs. Chromatin immunoprecipitation analysis reveals corecruitment of RORα and histone deacetylase 3 (HDAC3) on NF-κB target promoters and subsequent dismissal of CREB binding protein (CBP) and bromodomain-containing protein 4 (BRD4) for transcriptional repression. Together, we demonstrate that RORα/HDAC3-mediated attenuation of NF-κB 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).
Footnotes
↵1S.K.O. and D.K. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: dpark{at}ajou.ac.kr, sfang{at}yuhs.ac.kr, or sbaek{at}snu.ac.kr.
Author contributions: S.K.O., D.K., K.K., I.S.K., J.M.L., and S.H.B. designed research; S.K.O., D.K., K.K., S.-K.I., and S.F. performed research; S.K.O., K.K., K.B., Y.J., and H.L. contributed new reagents/analytic tools; S.K.O., D.K., K.K., Y.S.Y., S.-H.L., Y.K., D.P., and S.F. analyzed data; and S.K.O., D.K., D.P., S.F., and S.H.B. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE121977).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1907595116/-/DCSupplemental.
Published under the PNAS license.
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- Biological Sciences
- Immunology and Inflammation