Macrophaage lipid receptors in atherosclerosis

巨噬细胞被激活以产生炎性细胞因子，以响应各种外部刺激。其中一些最有效的刺激是从感染生物的细胞途径中提取的脂质。这些脂类激活细胞表面受体，然后参与下游负责诱导细胞因子表达基因表达的信号通路。最具代表性的受体信号通路之一是脂多糖结合蛋白(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与来自革兰氏阴性细菌最外层的脂多糖结合，并通过一种新描述的称为Toll受体(TLRs)的蛋白质家族激活信号级联。这会导致产生肿瘤坏死因子-α、白介素6和白介素1，它们是炎症反应的主要细胞因子效应因子。这种CD14启动的反应已被证明在革兰氏阴性败血症后败血症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内科疾病动脉粥样硬化的进展有关。衣原体是一种专性的细胞内寄生虫，存在于巨噬细胞内，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而在加速动脉粥样硬化斑块的发展中发挥作用，巨噬细胞泡沫细胞是早期动脉粥样硬化的组织学标志。在之前的授予期间，我们培育了缺乏CD14受体和LBP的动物。取自这些动物的巨噬细胞将被用来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衣原体感染动物的病变进展，CD14和LBP缺陷小鼠也将被用于研究这些途径与体内动脉粥样硬化形成的相关性。将巨噬细胞中的衣原体激活信号通路与肠道革兰氏阴性菌激活的信号通路进行比较，以分析CD14、LBP和TLRs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，以及更详细地了解感染因子对巨噬细胞的激活及其促炎细胞壁脂。

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.