Nur77 deficiency leads to systemic inflammation in elderly mice

Li, Xiu-Ming; Lu, Xing-Xing; Xu, Qian; Wang, Jingru; Zhang, Shen; Guo, Peng-Da; Li, Jianming; Wu, Hua

doi:10.1186/s12950-015-0085-0

Cited by 31 publications

(31 citation statements)

References 25 publications

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“…Recent studies have also shown that Nur77‐deficient mice are more susceptible to endotoxic shock . The elderly mice lacking Nur77 had severe systemic inflammation and elicited pro‐inflammatory M1 macrophages . In this study, we investigated the physiological relevance of Nur77 in IBD pathogenesis.…”

Section: Discussionmentioning

confidence: 97%

NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR–IL‐1R signalling axis

Wang

et al. 2015

The Journal of Pathology

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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.

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Section: Discussionmentioning

confidence: 97%

NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR–IL‐1R signalling axis

Wang

et al. 2015

The Journal of Pathology

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“…Lung tissues were collected for metastatic foci evaluation and standard histopathologic study. The details have been described recently (36)(37)(38). All animal experiments were approved by the Animal Care and Use Committee of Soochow University (Suzhou, Jiangsu, China).…”

Section: Xenograftsmentioning

confidence: 99%

RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway

Guo

Gan

et al. 2016

Cancer Research

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The Hippo-Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RARg as a regulator of the Hippo-Yap pathway in colorectal tumorigenesis and metastasis. RARg is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNM stage, and distant metastasis. Functional studies established that silencing of RARg drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo. Mechanistically, RARg controlled Hippo-Yap signaling to inhibit colorectal cancer development, acting to promote phosphorylation and binding of Lats1 to its transcriptional coactivator Yap and thereby inactivating Yap target gene expression. In clinical specimens, RARg expression correlated with overall survival outcomes and expression of critical Hippo-Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RARg as tumor suppressor in colorectal cancer that acts by restricting oncogenic signaling by the Hippo-Yap pathway, with potential implications for new approaches to colorectal cancer therapy.Cancer Res; 76(13); 3813-25. Ó2016 AACR.

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“…The biological functions of NR4A1 are complex and diverse and are often diametrically opposed. For instance, in the context of inflammation, NR4A1 deficiency leads to systemic inflammation in elderly mice, aggravates experimental colitis and hepatitis, and polarizes macrophages toward a pro‐inflammatory M1 phenotype, whereas retroviral overexpression of NR4A1 in macrophages activates the NF‐κB inflammatory pathway …”

Section: Introductionmentioning

confidence: 99%

The orphan nuclear receptor NR4A1 promotes FcεRI‐stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis

Jin

Deng

et al. 2019

Allergy

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Background: Nuclear receptor subfamily 4 group A member 1 (NR4A1), an orphan nuclear receptor, has been implicated in several biological events such as metabolism, apoptosis, and inflammation. Recent studies indicate a potential role for NR4A1 in mast cells, yet its role in allergic responses remains largely unknown.Objectives: The aim of this study was to clarify the role of NR4A1 in mast cell activation and anaphylaxis. Methods: To evaluate the function of NR4A1 in mast cells, the impacts of siRNA knockdown, gene knockout, adenoviral overexpression, and pharmacological inhibition of NR4A1 on FcεRI signaling and effector functions in mouse bone marrowderived mast cells (BMMCs) in vitro and on anaphylactic responses in vivo were evaluated. Results: Knockdown or knockout of NR4A1 markedly suppressed degranulation and lipid mediator production by FcεRI-crosslinked BMMCs, while its overexpression augmented these responses. Treatment with a NR4A1 antagonist also blocked mast cell activation to a similar extent as NR4A1 knockdown or knockout. Moreover, mast cell-specific NR4A1-deficient mice displayed dampened anaphylactic responses in vivo. Mechanistically, NR4A1 promoted FcεRI signaling by counteracting the liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) axis. Following FcεRI crosslinking, NR4A1 bound to the LKB1/AMPK complex and sequestered it in the nucleus, thereby promoting FcεRI downstream signaling pathways. Silencing or knockout of LKB1/AMPK largely abrogated the effect of NR4A1 on mast cell activation. Additionally, NR4A1 facilitated spleen tyrosine kinase activation independently of LKB1/AMPK.

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Nur77 deficiency leads to systemic inflammation in elderly mice

Cited by 31 publications

References 25 publications

NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR–IL‐1R signalling axis

NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR–IL‐1R signalling axis

RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway

The orphan nuclear receptor NR4A1 promotes FcεRI‐stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis

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