Macrophaage lipid receptors in atherosclerosis

巨噬细胞被激活产生炎性细胞因子，以响应各种外部刺激。这些刺激中最有效的是来自传染性生物体的细胞方式的脂质。这些脂质激活细胞表面受体，然后参与下游信号通路，负责诱导细胞因子表达基因表达。其中一个最具特征的受体信号通路涉及脂多糖结合蛋白（LBP）和CD14， CD14是一种55 kDa的糖基磷脂酰肌醇（GPI）连接蛋白，也以可溶性形式存在于血清中（sCD14）。CD14结合由LBP提供的脂多糖，这些脂多糖来源于革兰氏阴性菌的最外层，并通过新描述的Toll受体（TLRs）蛋白家族激活信号级联。这导致肿瘤坏死α (TNF- α)、白细胞介素-6 （IL-6）和白细胞介素-1（IL-1）的产生，这是炎症反应的主要细胞因子效应器。这种CD14启动反应已被证明在革兰氏阴性败血症后脓毒性休克的发病机制中起重要作用。另一种革兰氏阴性细菌。肺炎衣原体最近被认为与另一种重要的医学疾病——动脉粥样硬化的进展有关。衣原体是巨噬细胞内的专性细胞内寄生虫，最近的数据表明，衣原体的脂多糖可能通过促进巨噬细胞泡沫细胞的形成（早期动脉粥样硬化的组织学标志），在加速动脉粥样硬化斑块的发展中发挥作用。在之前的拨款奖励期，我们培育了缺乏CD14受体和LBP的动物。从这些动物身上提取的巨噬细胞将用于探索衣原体及其脂多糖外壳在感染和激活巨噬细胞中的作用。由于动脉粥样硬化小鼠模型可用于研究衣原体感染动物的病变进展，CD14和LBP缺陷小鼠也将用于研究这些途径与体内动脉粥样硬化的相关性。为了分析CD14、LBP和TLRs在这些不同感染中的作用，我们将比较巨噬细胞中衣原体激活的信号通路和肠内革兰氏阴性病原体参与的信号通路。这些研究将为衣原体诱导的动脉粥样硬化病变进展的生物学提供新的见解，并更详细地了解感染因子及其促炎细胞壁脂质的巨噬细胞活化。

Macrophages are activated to produce inflammatory cytokines in response to a variety of external stimuli. Some of the most potent of these stimuli are lipids derived from the cell ways of infectious organisms. These lipids activate cell surface receptors than then engage downstream signaling pathways responsible for the induction of cytokine expression gene expression. One of the best characterized of the receptor signaling pathways involves lipopolysaccharide binding protein (LBP) and CD14, a 55 kDa glycosyl phosphatidylinositol (GPI)-linked protein that is also present in a soluble form (sCD14) in serum. CD14 binds lipopolysaccharides, presented to it by LBP, that are derived from the outermost layer of Gram-negative bacteria and activates a signaling cascade via a newly described family of protein called Toll receptors (TLRs). This results in the production of tumor necrosis-alpha (TNF- alpha) interleukin-6 (IL-6), and interleukin-1(IL-1), major cytokine effectors of the inflammatory response. This CD14 initiated response has been shown to be important in the pathogenesis of septic shock following Gram-negative septicemia. Another Gram negative bacteria. Chlamydia pneumoniae, has recently been implicated in the progression of an another important medical disease, atherosclerosis. Chlamydia is an obligate intracellular parasite that resides within macrophages and recent data has suggested that the lipopolysaccharides from Chlamydia may play a role in accelerating atherosclerotic plaque development by enhancing the formation of the macrophage foam cell, the histologic hallmark of the early atheroma. In the previous grant award period, we generated animals lacking the CD14 receptor and LBP. Macrophages taken from these animals will be used to explore the role of Chlamydia and its lipopolysaccharide coat in infecting and activating macrophages. As mouse models of atherosclerosis can be used to study the progression of lesions in animals infected with Chlamydial organisms, the CD14 and LBP deficient mice will also be used to perform studies of the relevance of these pathways to atherogenesis in vivo. Comparisons will be made of the Chlamydial activating signaling pathways in macrophages to those pathways engaged by enteric Gram negative pathogens in order to analyze the roles of CD14, LBP, and TLRs in these differing infection. These studies should provide new insights into the biology of Chlamydia- induced atherosclerotic lesion progression as well as more detailed understanding of macrophage activation by infectious agents and their pro-inflammatory cell wall lipids.