Macrophaage lipid receptors in atherosclerosis

巨噬细胞被激活以响应各种外部刺激而产生炎性细胞因子。这些刺激中最有效的一些是来自感染性生物体细胞途径的脂质。这些脂质激活细胞表面受体，然后参与负责诱导细胞因子表达基因表达的下游信号通路。最佳表征的受体信号传导途径之一涉及脂多糖结合蛋白（LBP）和CD 14，CD 14是一种55 kDa糖基磷脂酰肌醇（GPI）连接蛋白，也以可溶性形式（sCD 14）存在于血清中。CD 14结合由LBP呈递给它的脂多糖，这些脂多糖来自革兰氏阴性菌的最外层，并通过一种新描述的称为Toll受体（TLR）的蛋白质家族激活信号级联。这导致产生肿瘤坏死-α（TNF-α）白细胞介素-6（IL-6）和白细胞介素-1（IL-1），它们是炎症反应的主要细胞因子效应物。这种CD 14启动的应答已被证明在革兰氏阴性败血症后的脓毒性休克的发病机制中是重要的。另一种革兰氏阴性菌。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。衣原体是一种专性细胞内寄生虫，存在于巨噬细胞内，最近的数据表明，来自衣原体的脂多糖可能通过增强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发展中发挥作用。在上一个资助期，我们产生了缺乏CD 14受体和LBP的动物。从这些动物中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。由于动脉粥样硬化的小鼠模型可用于研究感染衣原体生物体的动物中病变的进展，因此CD 14 和LBP缺陷小鼠也将用于进行这些途径与体内动脉粥样硬化形成的相关性的研究。将巨噬细胞中的衣原体激活信号传导途径与肠道革兰氏阴性病原体参与的那些途径进行比较，以分析CD 14、LBP和TLR在这些不同感染中的作用。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对巨噬细胞的激活。

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.