Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Abstract

Allergic asthma is characterized by persistent chronic airway inflammation, which leads to mucus hypersecretion and airway hyperresponsiveness. Nuclear receptor Nur77 plays a pivotal role in distinct immune and inflammatory cells and is expressed in eosinophils and lung epithelium. However, the role of Nur77 in allergic airway inflammation has not been studied so far. In the present study, we determined the role of Nur77 in airway inflammation using a murine model of OVA-induced allergic airway inflammation. We found that OVA-challenged Nur77 knockout (KO) mice show significantly enhanced infiltration of inflammatory cells, including eosinophils and lymphocytes, and aggravated mucus production. The infiltration of macrophages is limited in this model and was similar in wild-type and Nur77 KO mice. Higher levels of Th2 cytokines were found in bronchoalveolar lavage fluid and draining lymph node cells of Nur77-KO mice, as well as increased serum IgG1 and IgG2a levels. Knockdown of Nur77 in human lung epithelial cells resulted in a marked increase in IκBα phosphorylation, corresponding with elevated NF-κB activity, whereas Nur77 overexpression decreased NF-κB activity. Consistently, Nur77 significantly decreased mRNA levels of inflammatory cytokines and Muc5ac expression and also attenuated mucus production in lung epithelial cells. To further corroborate these findings, we searched for association of single nucleotide polymorphisms in Nur77 gene with asthma and with the severity of bronchial hyperresponsiveness. We identified three Nur77 single nucleotide polymorphisms showing association with severity of bronchial hyperresponsiveness in asthma patients. Collectively, these findings support a protective role of Nur77 in OVA-induced airway inflammation and identify Nur77 as a novel therapeutic target for airway inflammation.

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

“…Tnfrsf8 , Anxa2 and Il1r2 are overexpressed in allergic asthmatics 33–35 . Deletion of Nr4a1 , which is downregulated by IL-25 combined with NMU, exacerbates airway inflammation in mice, suggesting a potential role in limiting inflammatory ILC responses 36 .…”

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). …”

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma

“…An LXR agonist reduces the response to OVA-allergen challenge in a murine model of asthma [17]. NR4A attenuates airway inflammation in a mouse model of asthma [18]. These data suggest that RXRs, which act as both homodimers and heterodimers with other NRs, may be potential targets in the prevention and management of heterogeneous asthma patients.…”