Nuclear receptors Nur77, Nurr1, and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses
Nuclear receptors Nur77, Nurr1, and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses
复制标题
DOI：
10.1161/01.atv.0000238346.84458.5d
复制
发表时间：
2006-10-01
影响因子：
8.7
通讯作者：
de Vries, Carlie J. M.
中科院分区：
文献类型：
--
作者：
Bonta, Peter I.;van Tiel, Claudia M.;de Vries, Carlie J. M.
目的-动脉粥样硬化是一种炎症性疾病，巨噬细胞活化和脂质负荷在其中起着至关重要的作用。在这项研究中，我们研究了NR4A核受体家族，包括Nur77 (NR4A1, TR3), Nurr1 （NR4A2）和NOR-1 （NR4A3）在人巨噬细胞中的表达和功能。方法和结果-原位杂交和免疫组织化学检测发现，Nur77、Nurr1和NOR-1在早期和晚期人类动脉粥样硬化病变巨噬细胞中主要在斑块激活/进展区域表达。蛋白表达局限于细胞核。原代巨噬细胞和THP-1巨噬细胞在脂多糖和肿瘤坏死因子α的作用下短暂表达nr4a因子。慢病毒过度表达Nur77、Nurr1或NOR-1会降低白细胞介素(IL)-1 β和IL-6促炎细胞因子、IL-8、巨噬细胞炎症蛋白-1 α和-1 β以及单核细胞趋化蛋白-1趋化因子的表达和产生。此外，nr4a因子减少氧化低密度脂蛋白摄取，这与巨噬细胞标记基因清道夫受体- a、CD36和CD11b的下调一致。用基因特异性慢病毒短发夹rna敲低Nur77或NOR-1导致细胞因子和趋化因子合成增强，脂质负荷增加，CD11b表达增强，证明内源性nr4a因子抑制巨噬细胞活化、泡沫细胞形成和分化。结论- nr4a因子在人动脉粥样硬化病变巨噬细胞中表达，降低人巨噬细胞脂质负荷和炎症反应，进一步证明nr4a因子在动脉粥样硬化中的保护作用。
Objective - Atherosclerosis is an inflammatory disease in which macrophage activation and lipid loading play a crucial role. In this study, we investigated expression and function of the NR4A nuclear receptor family, comprising Nur77 (NR4A1, TR3), Nurr1 (NR4A2), and NOR-1 (NR4A3) in human macrophages.Methods and Results - Nur77, Nurr1, and NOR-1 are expressed in early and advanced human atherosclerotic lesion macrophages primarily in areas of plaque activation/progression as detected by in situ-hybridization and immunohistochemistry. Protein expression localizes to the nucleus. Primary and THP-1 macrophages transiently express NR4A-factors in response to lipopolysaccharide and tumor necrosis factor alpha. Lentiviral overexpression of Nur77, Nurr1, or NOR-1 reduces expression and production of interleukin (IL)-1 beta and IL-6 proinflammatory cytokines and IL-8, macrophage inflammatory protein-1 alpha and -1 beta and monocyte chemoattractant protein-1 chemokines. In addition, NR4A-factors reduce oxidized-low-density lipoprotein uptake, consistent with downregulation of scavenger receptor-A, CD36, and CD11b macrophage marker genes. Knockdown of Nur77 or NOR-1 with gene-specific lentiviral short-hairpin RNAs resulted in enhanced cytokine and chemokine synthesis, increased lipid loading, and augmented CD11b expression, demonstrating endogenous NR4A-factors to inhibit macrophage activation, foam-cell formation, and differentiation.Conclusion - NR4A-factors are expressed in human atherosclerotic lesion macrophages and reduce human macrophage lipid loading and inflammatory responses, providing further evidence for a protective role of NR4A-factors in atherogenesis.