Fontaine Coralie, Rigamonti Elena, Nohara Atsushi, Gervois Philippe, Teissier Elisabeth, Fruchart Jean-Charles, Staels Bart, Chinetti-Gbaguidi Giulia
Institut Pasteur de Lille, Département d'Athérosclérose, Lille, France.
Circ Res. 2007 Jul 6;101(1):40-9. doi: 10.1161/CIRCRESAHA.106.135814. Epub 2007 May 31.
Macrophages play a central role in host defense against pathogen microbes by recognizing bacterial components, resulting in the activation of an arsenal of anti-microbial effectors. Toll-like receptor (TLR)-4 mediates the recognition of lipopolysaccharide, a pathogen-associated molecular pattern from gram-negative bacteria. Activation of the TLR-4 signaling pathway by lipopolysaccharide increases antibacterial effects by inducing secretion of cytokines that activate an immune inflammatory response and by generating bactericidal reactive oxygen species via the NADPH oxidase system. Liver X Receptors (LXRs) are nuclear receptors controlling cholesterol homeostasis and inflammation in macrophages. In addition, LXRs are critical for macrophage survival and play a role in the innate immune response in the mouse. In this study, we investigated whether LXR activation also regulates host defense mechanisms in human macrophages. In primary human macrophages, oxidized LDL and synthetic LXR ligands increased TLR-4 gene expression. Transient transfection assays, gel shift and chromatin immunoprecipitation analysis indicated that LXRs induce human TLR-4 promoter activity by binding to a DR4-type LXR response element. LXR induction of TLR-4 mRNA was followed by an induction of TLR-4 protein expression. Moreover, although short-term pretreatment with LXR agonists significantly reduced the inflammatory response induced by lipopolysaccharide, pretreatment of macrophages for 48 hours with LXR agonists resulted in an enhanced lipopolysaccharide response. Finally, LXR activation increased reactive oxygen species generation by enhancing the expression of NADPH oxidase subunits. These data provide evidence for an immunomodulatory function of LXRs in human macrophages via mechanisms distinct from those previously identified in mouse macrophages.
巨噬细胞在宿主抵御病原微生物的防御过程中发挥着核心作用，通过识别细菌成分，从而激活一系列抗菌效应器。Toll样受体（TLR）-4介导对脂多糖的识别，脂多糖是革兰氏阴性菌的一种病原体相关分子模式。脂多糖激活TLR-4信号通路可通过诱导激活免疫炎症反应的细胞因子分泌以及通过NADPH氧化酶系统产生活菌活性氧来增强抗菌作用。肝脏X受体（LXRs）是控制巨噬细胞胆固醇稳态和炎症的核受体。此外，LXRs对巨噬细胞存活至关重要，并在小鼠的先天免疫反应中发挥作用。在本研究中，我们调查了LXR激活是否也调节人类巨噬细胞中的宿主防御机制。在原代人巨噬细胞中，氧化型低密度脂蛋白和合成LXR配体可增加TLR-4基因表达。瞬时转染试验、凝胶迁移和染色质免疫沉淀分析表明，LXRs通过与DR4型LXR反应元件结合来诱导人类TLR-4启动子活性。LXR诱导TLR-4 mRNA后，接着诱导TLR-4蛋白表达。此外，尽管用LXR激动剂进行短期预处理可显著降低脂多糖诱导的炎症反应，但用LXR激动剂对巨噬细胞进行48小时预处理则导致脂多糖反应增强。最后，LXR激活通过增强NADPH氧化酶亚基的表达来增加活性氧的产生。这些数据为LXRs在人类巨噬细胞中通过不同于先前在小鼠巨噬细胞中鉴定的机制发挥免疫调节功能提供了证据。
