Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFκB Activity in Macrophages.
Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFκB Activity in Macrophages.
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DOI：
10.1371/journal.pone.0133598
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
de Vries CJ
中科院分区：
文献类型：
--
作者：
Hamers AA;van Dam L;Teixeira Duarte JM;Vos M;Marinković G;van Tiel CM;Meijer SL;van Stalborch AM;Huveneers S;Te Velde AA;de Jonge WJ;de Vries CJ
核受体Nur77，又称NR4A1或TR3，在先天免疫和获得性免疫中发挥重要作用。Nur77在调节T辅助细胞1/调节性T细胞平衡中起关键作用，在巨噬细胞中表达，并驱动M2巨噬细胞极化。在本研究中，我们旨在明确Nur77在炎症性肠病中的作用。在野生型和Nur77-/-小鼠中，研究了葡聚糖硫酸钠(DSS)和2，4，6-三硝基苯磺酸(TNBS)诱导的结肠炎的发展。为了了解其潜在的机制，Nur77在巨噬细胞和肠上皮细胞中过表达。在克罗恩病和溃疡性结肠炎患者的结肠组织和结肠炎小鼠的结肠组织中，Nur77蛋白在炎性细胞和上皮细胞中表达。在两种小鼠结肠炎模型中，Nur77-/-小鼠的炎症增加。经DSS治疗后，Nur77缺陷结肠中性粒细胞内流增加，IL-6、MCP-1和KC产生增加。与野生型小鼠相比，肿瘤坏死因子诱导的T细胞和炎性单核细胞进入结肠的数量增加，单核细胞趋化蛋白-1、肿瘤坏死因子α和IL-6的表达增加，Foxp3RNA的表达降低。在脂多糖激活的巨噬细胞中过表达Nur77可上调IL-10，并通过抑制核因子αB抑制肿瘤坏死因子κ-1和单核细胞趋化蛋白-1mRNA的表达。NUR77还显著降低肠上皮Caco-2细胞单核细胞趋化蛋白-1、CXCL-1、IL-8、巨噬细胞炎性蛋白-1α和肿瘤坏死因子α的表达。NUR77过表达抑制巨噬细胞和肠上皮细胞的炎症状态，与体内小鼠数据一起支持NUR77在实验性结肠炎中具有保护作用。这些发现可能对开发针对炎症性肠病和其他炎症性疾病的新的靶向治疗策略具有指导意义。
Nuclear receptor Nur77, also referred to as NR4A1 or TR3, plays an important role in innate and adaptive immunity. Nur77 is crucial in regulating the T helper 1/regulatory T-cell balance, is expressed in macrophages and drives M2 macrophage polarization. In this study we aimed to define the function of Nur77 in inflammatory bowel disease. In wild-type and Nur77-/- mice, colitis development was studied in dextran sodium sulphate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced models. To understand the underlying mechanism, Nur77 was overexpressed in macrophages and gut epithelial cells. Nur77 protein is expressed in colon tissues from Crohn’s disease and Ulcerative colitis patients and colons from colitic mice in inflammatory cells and epithelium. In both mouse colitis models inflammation was increased in Nur77-/- mice. A higher neutrophil influx and enhanced IL-6, MCP-1 and KC production was observed in Nur77-deficient colons after DSS-treatment. TNBS-induced influx of T-cells and inflammatory monocytes into the colon was higher in Nur77-/- mice, along with increased expression of MCP-1, TNFα and IL-6, and decreased Foxp3 RNA expression, compared to wild-type mice. Overexpression of Nur77 in lipopolysaccharide activated RAW macrophages resulted in up-regulated IL-10 and downregulated TNFα, MIF-1 and MCP-1 mRNA expression through NFκB repression. Nur77 also strongly decreased expression of MCP-1, CXCL1, IL-8, MIP-1α and TNFα in gut epithelial Caco-2 cells. Nur77 overexpression suppresses the inflammatory status of both macrophages and gut epithelial cells and together with the in vivo mouse data this supports that Nur77 has a protective function in experimental colitis. These findings may have implications for development of novel targeted treatment strategies regarding inflammatory bowel disease and other inflammatory diseases.