Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells
Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells
复制标题
DOI：
10.4049/jimmunol.1401714
复制
发表时间：
2015-08-15
影响因子：
4.4
通讯作者：
de Vries, Carlie J. M.
中科院分区：
文献类型：
--
作者：
Kurakula, Kondababu;Vos, Mariska;de Vries, Carlie J. M.
变应性哮喘的特征是持续的慢性气道炎症，导致粘液分泌过多和气道高反应性。核受体Nur77在不同的免疫和炎症细胞中起关键作用，并在嗜酸性粒细胞和肺上皮中表达。然而，Nur77在变应性气道炎症中的作用至今未见研究。在本研究中，我们通过ova诱导的小鼠变应性气道炎症模型来确定Nur77在气道炎症中的作用。我们发现，ova激发的Nur77基因敲除（KO）小鼠炎症细胞（包括嗜酸性粒细胞和淋巴细胞）的浸润显著增强，粘液生成加剧。巨噬细胞的浸润在该模型中是有限的，在野生型和Nur77 KO小鼠中类似。在Nur77-KO小鼠支气管肺泡灌洗液和引流淋巴结细胞中发现Th2细胞因子水平升高，血清IgG1和IgG2a水平升高。在人肺上皮细胞中，敲低Nur77导致I κ B α磷酸化显著增加，与nf - κ B活性升高相对应，而Nur77过表达则降低NF-kB活性。与此一致，Nur77显著降低炎症细胞因子mRNA水平和Muc5ac表达，并减弱肺上皮细胞粘液产生。为了进一步证实这些发现，我们寻找Nur77基因单核苷酸多态性与哮喘和支气管高反应性严重程度的关联。我们确定了三个Nur77单核苷酸多态性，显示与哮喘患者支气管高反应性的严重程度有关。总的来说，这些发现支持Nur77在ova诱导的气道炎症中的保护作用，并确定Nur77是气道炎症的新治疗靶点。
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 I kappa B alpha phosphorylation, corresponding with elevated NF-kappa B activity, whereas Nur77 overexpression decreased NF-kB 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.