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.

Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model

“…CsnB, a pharmacological activator of Nur77 (44, 97), has been shown to exhibit anti-inflammatory effects in inflammatory bowel disease (89) and in cholesterol-induced THP-1 and U937 cells (91). Our data demonstrated therapeutic effects of CsnB against ARDS and that downregulation of ET-1 may contribute to suppression of pulmonary neutrophilic inflammation by CsnB, resulting in alleviation of endothelial-epithelial barrier dysfunction and improvement of hypoxemia and multiple organ injury.…”

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy

“…Recent interest has focused on its potent anti-inflammatory effect in inflammatory diseases and cancer. Genetic studies have revealed a critical role of Nur77 in controlling the inflammatory responses, highlighted by its protective function in atherosclerosis (Hamers et al, 2012; Hanna et al, 2012), obesity (Perez-Sieira et al, 2013), diabetes (Chao et al, 2009), asthma (Kurakula et al, 2015), arthritis (De Silva et al, 2005), and inflammatory bowel disease (Hamers et al, 2015; Wu et al, 2016). …”

NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells

“…As orphan receptors, they have no known endogenous ligand(s) and are regulated primarily at the level of gene transcription, posttranslational modifications, and protein–protein interactions (1–3). However, these receptors can be activated by select exogenous agents such as the photochemical-based compound 1,1-bis (3′-indolyl)-1-( p -chlorophenyl) methane (C-DIM12), an NR4A2 activator, and the fungal metabolite Cytosporone-B (Csn-B), an NR4A1 agonist (4–6). These receptors control and limit inflammatory responses primarily by acting as feedback regulators of NF-κB signaling, and more recently have been identified as promoters of inflammatory resolution processes (1–3, 7).…”