Pathological Significance of Macrophage Scavenger Receptors

1.本实验室制备了抗人巨噬细胞清道夫受体(MSR)单抗和MSR合成肽多克隆抗体。利用这些抗体，我们的免疫组织化学和免疫电子显微镜研究表明，MSR分布在巨噬细胞的细胞膜上，广泛分布于人类各种器官和组织中。结果：1.用抗牛和抗鼠MSR单抗进行免疫组织化学和免疫电子显微镜观察，发现MSR在牛和小鼠组织中的分布和亚细胞定位相似。我们的研究表明，在人类、牛和小鼠身上，MSR可以与修饰的低密度脂蛋白(LDL)结合，如乙酰化低密度脂蛋白(AcLDL)或氧化型低密度脂蛋白(OxLDL)，以及晚期糖基化终末产物(AGE)。MSR缺陷小鼠对acLDL、oxLDL和AGE的摄取显著减少。在人动脉粥样硬化病变中，巨噬细胞源性泡沫细胞表达MSR，细胞内聚集oxLDL和AGE。在apo-E/MSR双基因敲除小鼠和饮食诱导的低密度脂蛋白受体/MSR双基因敲除小鼠中，与apo-E或饮食诱导的低密度脂蛋白受体单基因敲除小鼠相比，动脉粥样硬化斑块明显缩小，表明MSR与动脉粥样硬化的发生密切相关。与野生型小鼠相比，MSR缺陷小鼠静脉注射热灭活小棒状杆菌(C.parvum)诱导的肝脏肉芽肿形成延迟，Kupffer细胞摄取微小棒状杆菌明显受损，尤其是在早期。这些结果表明，MSR参与了抵御外源入侵细菌的防御机制。

1. Anti-human monoclonal antibodies for macrophage scavenger receptors (MSR), as well as polyclonal antibodies for synthetic peptides of MSR, were generated in our laboratory. Using these antibodies, our immunohistochemical and immunoelectron microscopic studies demonstrated that MSR was distributed on the cell membranes of macrophages ubiquitously distributed in various organs and tissues of humans. Immunohistochemical and immunoelectron microscopic investigation with anti-bovine or anti-murine MSR monoclonal antibodies revealed similar distribution and subcellar localization of MSR in bovine and murine tissues.2. Our studies demonstrated in humans, bovines, and mice that MSR can bind to modified low density lipoproteins (LDL) such as acetylated LDL (acLDL) or oxidized LDL (oxLDL) and to advanced glycation end products (AGE). MSR-deficient mice revealed marked reductions in the uptake of acLDL, oxLDL, and AGE.3. In atheroselerotic lesions of human aorta, macrophage-derived foam cells showed the expression of MSR and intracellular accumulation of oxLDL and AGE.In apo-E/MSR double knockout mice and diet-induced LDL receptor/MSR double knockout mice, the lesion size of atheroselerosis was markedly reduced in the aorta, compared with apo-E or diet-induced LDL receptor-single knockout mice, indicating that MSR is deeply implicated in atherognesis.4. Compared with the wild-type mice, the hepatic granuloma formation induced by intravenous injection of heat-killed Corynebacterium parvum (C.parvum) was delayed and the uptake of C.parvum by Kupffer cells was markedly impaire in MSR-deficient mice, particularly in the early stage. These results indicate that MSR is involved in the defense mechanisms against exogenously invading bacteria.