IN VIVO EXPRESSION AND PATHOLOGICAL ROLES OF SCAVENGER RECEPTOR FAMILY MOLECULES

清道夫受体家族分子的体内表达和病理作用

• 批准号: 13470052
• 负责人: TAKEYA Motohiro
• 金额: $ 9.02万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470052/
• 关键词: Scavenger receptor family; Class A scavenger receptor I.II (CD204); MARCO receptor; LOX-1; nonalocoholic steatohepatitis; macrophages; tissue distribution; monoclonal antibodies; スカベンジャー受容体ファミリー; SR-AI,II (CD204); 高脂血症; 胎盤; 免疫組織化学; SR-AI.II(C

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.

清道夫受体 (SR) 是细胞表面糖蛋白家族，能够结合修饰的 LDL，例如乙酰化 LDL 和氧化 LDL。目前，SR家族分子分为A类至F类六类。为了研究SR原型人类A类清道夫受体I型、II型（SR-AI，II）在体内的分布和作用，我们生产了高度特异性的单克隆抗体。使用这些抗体，发现 SR-AI,II 在大多数组织巨噬细胞上表达，例如肝脏的库普弗细胞、肺泡巨噬细胞、淋巴结的鼻窦细胞和脾红髓巨噬细胞。在病理条件下，炎症组织中的浸润巨噬细胞，包括构成各种肉芽肿的巨噬细胞、阿尔茨海默病中的小胶质细胞以及动脉粥样硬化中的载脂巨噬细胞，均被阳性标记。在用 GM-CSF 和 IL-4 处理的 10-15% 的单核细胞来源的树突状细胞中也发现了 SR-AI,II 表达。这些结果表明 SR-AI,II 在先天性和获得性免疫以及动脉粥样硬化形成中发挥重要作用。通过这些观察，SR-AI,II在第七届人类白细胞分化抗原研讨会上被指定为新的CD分子CD204。MARCO（具有胶原结构的巨噬细胞受体）是A-SR类的另一个成员，据报道是由LPS刺激诱导的。我们观察到非酒精性脂肪性肝炎中 Kupffer 细胞上 MARCO 的诱导，并表明门静脉循环中内毒素水平升高会在肝脏中诱导 MARCO。揭示MARCO在非酒精性脂肪性肝炎中的作用的项目正在进行中。为了探讨E类SR的LOX-1（凝集素样氧化LDL受体-1）在动脉粥样硬化形成中的作用，我们使用LOX-1缺陷小鼠研究了病变发展。然而，到目前为止，与对照小鼠相比，尚未观察到病变发展的显着差异。

项目成果

Tomokiyo R, Jinnouchi K, Honda M, Wada Y, Hanada N, Hiraoka T, Suzuki H, Kodama T, Takahashi K, Takeya M.: "Production, characterization, and interspecies reactivities of monoclonal antibodies against human class A macrophage scavenger receptors."Atherosc

Tomokiyo R、Jinnouchi K、Honda M、Wada Y、Hanada N、Hiraoka T、Suzuki H、Kodama T、Takahashi K、Takeya M.：“针对人 A 类巨噬细胞清道夫受体的单克隆抗体的生产、表征和种间反应性。

Nakamura R, Egashira K, Machida Y, Hayashidani S, Takeya M, Utsumi H, Tsutsui H, Takeshita A.: "Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure : roles of oxidative stress and inflammation."Circulation.

Nakamura R、Egashira K、Machida Y、Hayashidani S、Takeya M、Utsumi H、Ttsutsui H、Takeshita A.：“普罗布考可减轻心动过速引起的心力衰竭中的左心室功能障碍和重塑：氧化应激和炎症的作用。”循环。

Uesugi N et al.: "Glycoxidation-modified macrophages and lipid peroxidation products are associated with the progression of human diabetic nephropathy"Am J Kidney Dis. 98. 1016-1025 (2001)

Uesugi N 等人：“糖氧化修饰的巨噬细胞和脂质过氧化产物与人类糖尿病肾病的进展有关”Am J Kidney Dis。

Jinnouchi K, Terasaki Y, Fujiyama S, Tomita K, Kuziel WA, Maeda N, Takahashi K, Takeya M.: "Impaired hepatic granuloma formation in mice deficient in C-C chemokine receptor 2."J Pathol. 200. 406-416 (2003)

Jinnouchi K、Terasaki Y、Fujiyama S、Tomita K、Kuziel WA、Maeda N、Takahashi K、Takeya M.：“缺乏 C-C 趋化因子受体 2 的小鼠肝肉芽肿形成受损。”J Pathol。

Takeya M, Tomokiyo R, Jinnouchi K, Honda M, Wada Y, Suzuki H, Kodama T, Takahashi K.: "CD204 : Macrophage scavenger receptor, a new differentiation marker for macrophages."Leucocyte Typing VII, White Cell Differentiation Anitgens (Mason D et al. eds), Oxf

Takeya M、Tomokiyo R、Jinnouchi K、Honda M、Wada Y、Suzuki H、Kodama T、Takahashi K.：“CD204：巨噬细胞清道夫受体，巨噬细胞的新分化标记。”白细胞分型 VII，白细胞分化抗原（Mason）