IN VIVO EXPRESSION AND PATHOLOGICAL ROLES OF SCAVENGER RECEPTOR FAMILY MOLECULES

清道夫受体(SRS)是一类能结合乙酰化低密度脂蛋白和氧化型低密度脂蛋白等修饰低密度脂蛋白的细胞表面糖蛋白家族。目前，SR家族分子分为六类，即A类到F类。为了检测人类A类清道夫受体I，II(SR-AI，II)在体内的分布和作用，我们制备了高度特异的单抗。利用这些抗体，发现SR-AI、II在大多数组织巨噬细胞如肝脏Kupffer细胞、肺泡巨噬细胞、淋巴结窦上皮细胞和脾红髓巨噬细胞上有结构性表达。在病理条件下，炎性组织中的巨噬细胞(包括构成各种肉芽肿的巨噬细胞)、阿尔茨海默病的小胶质细胞和动脉粥样硬化中的高脂巨噬细胞呈阳性标记。在GM-CSF和IL-4处理的单核细胞来源的树突状细胞中，也有10-15%的细胞表达SR-AI、II。这些结果表明，SR-AI、II在先天免疫、获得性免疫以及动脉粥样硬化的形成中都起着重要作用。通过这些观察，SR-AI，II已经在第七届人类白细胞分化抗原研讨会上被确定为一个新的CD分子CD204。MARCO(具有胶原性结构的巨噬细胞受体)是A-SR的另一个成员，据报道是由内毒素刺激诱导的。我们观察了MARCO对非酒精性脂肪性肝炎Kupffer细胞的诱导作用，发现门静脉循环内毒素水平升高可诱导肝脏MARCO的产生。为了揭示Marco在非酒精性脂肪性肝炎中的作用，我们利用LOX-1基因缺陷小鼠研究了LOX-1基因缺陷小鼠的病变发展，以探讨凝集素样氧化低密度脂蛋白受体-1在动脉粥样硬化形成中的作用。然而，到目前为止，还没有观察到与对照小鼠相比在病变发展方面的显著差异。

Scavenger receptors (SRs) are a family of cell surface glycoproteins able to bind modified LDLs such as acetylated LDL and oxidized LDL. Currently, SR family molecules are classified into six groups, namely class A to class F. To examine the in vivo distribution and the roles of human class A scavenger receptor Type I, II (SR-AI,II), a prototype of SRs, we have produced highly-specific monoclonal antibodies. Using these antibodies, SR-AI,II was found to be expressed constitutionally on most tissue macrophages such as Kupffer cells of the liver, alveolar macrophages, sinushsitiocytes of lymph nodes and splenic red pulp macrophages. In pathological conditions, infiltrated macrophages in inflammatory tissues including those composing various kinds of granulomas, microglial cells in Alzheimer's disease, and lipid-laden macrophages in atherosclerosis were positively labeled. SR-AI,II expression was also found in 10-15 % of monocyte-derived dendritic cells treated with GM-CSF and IL-4. These results indicate that SR-AI,II plays important roles both in innate and acquired immunities as well as atherogenesis. Through these observations, SR-AI,II has been assigned as a new CD molecule, CD204, at VIIth Workshop of Human leukocyte Differentiation Antigen.MARCO (macrophage receptor with a collagenous structure), an another member of Class A-SR, was reported to be induced by LPS stimulation. We have observed the induction of MARCO on Kupffer cells in non-alcoholic steatohepatitis, and shown that elevated endotoxin level in portal circulation induces MARCO in the liver. A project to disclose the role of MARCO in non-alcoholic steatohepatitis in now on progress.To explore the role of LOX-1 (lectin-like oxidized LDL receptor-1), a class E SR, in atherogenesis, we have studied the lesion development using LOX-1-deficient mice. So far, however, no significant difference in lesion development compared to control mice has been observed.