Pathological Significance of Macrophage Scavenger Receptors

1. 本实验室制备了巨噬细胞清道夫受体（macrophage scavenger receptor， MSR）的抗人单克隆抗体，以及巨噬细胞清道夫受体合成肽的多克隆抗体。利用这些抗体，我们的免疫组织化学和免疫电镜研究表明，MSR分布在巨噬细胞的细胞膜上，巨噬细胞普遍分布在人体的各个器官和组织中。用抗牛或抗鼠MSR单克隆抗体进行免疫组化和免疫电镜观察发现，MSR在牛和鼠组织中的分布和亚细胞定位相似。我们在人类、牛和小鼠身上的研究表明，MSR可以结合修饰的低密度脂蛋白（LDL），如乙酰化LDL （acLDL）或氧化LDL (oxLDL)，以及晚期糖基化终产物（AGE）。msr缺陷小鼠显示acLDL、oxLDL和age的摄取明显减少。在人主动脉动脉粥样硬化病变中，巨噬细胞来源的泡沫细胞表达MSR，细胞内oxLDL和AGE积累。在载脂蛋白e /MSR双敲除小鼠和饮食诱导的LDL受体/MSR双敲除小鼠中，与载脂蛋白e或饮食诱导的LDL受体单敲除小鼠相比，主动脉动脉粥样硬化的病变大小明显减小，表明MSR与动脉粥样硬化密切相关。与野生型小鼠相比，静脉注射热杀细小棒状杆菌（C.parvum）诱导的肝肉芽肿形成延迟，Kupffer细胞对细小棒状杆菌的摄取明显减弱，尤其是在早期。这些结果表明MSR参与了对外源细菌入侵的防御机制。

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.