title: NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR-IL-1R signalling axis.
abstract: Nur77, an immediate-early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC-approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome-wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS-induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn-B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS-induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR-IL-1R signalling by interacting with TRAF6. This interaction prevented auto-ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF-κB activation and pro-inflammatory cytokine production. Taken together, our GWAS-based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR-IL-1R-initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD.
authors.affiliation: Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.affiliation: Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.
authors.forename: Xiu-Ming
authors.initials: XM
authors.lastname: Li
authors.affiliation: Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.|First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Gan
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, People's Republic of China.
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Jiang
authors.affiliation: Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, People's Republic of China.
authors.forename: Xin-Dao
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.
authors.forename: Xiao-Shun
authors.initials: XS
authors.lastname: He
authors.affiliation: Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.
authors.forename: Xing-Xing
authors.initials: XX
authors.lastname: Lu
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, People's Republic of China.|Sanford-Burnham Medical Research Institute, Cancer Center, La Jolla, CA, USA.
authors.forename: Yan-Bing
authors.initials: YB
authors.lastname: Guo
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, People's Republic of China.|Sanford-Burnham Medical Research Institute, Cancer Center, La Jolla, CA, USA.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Zhang
authors.affiliation: Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D003093:Colitis, Ulcerative / Q000235:genetics*; D003106:Colon / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics*; D016264:Dextran Sulfate / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D010648:Phenylacetates / Q000494:pharmacology; D011446:Prospective Studies; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010648:Phenylacetates; D017472:Receptors, Interleukin-1; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; C531461:cytosporone B; D016264:Dextran Sulfate
keywords: Nur77; TLR-IL-1R signalling; inflammation; inflammatory bowel disease; mouse model