Sir William Dunn School of Pathology, Department of Biochemistry, University of Oxford,South Parks Road, Oxford OX13RE, United Kingdom.
Biochemistry. 2009 Dec 22;48(50):11858-71. doi: 10.1021/bi9013769.
Macrophage scavenger receptor A (SR-A) is a multifunctional, multiligand pattern recognition receptor with roles in innate immunity, apoptotic cell clearance, and age-related degenerative pathologies, such as atherosclerosis and Alzheimer's disease. Known endogenous SR-A ligands are polyanionic and include modified lipoproteins, advanced glycation end products, and extracellular matrix proteins. No native plasma ligands have been identified, but it is known that SR-A recognition of unidentified serum components mediates integrin-independent macrophage adhesion, which may drive chronic local inflammation. In this study, we used a high-throughput fractionation and screening method to identify novel endogenous SR-A ligands that may mediate macrophage adhesion. SR-A was found to recognize the exchangeable apolipoproteins A-I and E (apo A-I and apo E, respectively) in both lipid-free and lipid-associated form, suggesting the shared amphipathic alpha-helix as a potential recognition motif. Adhesion of RAW 264.7 macrophages to surfaces coated with apo A-I and apo E4 proved to be integrin-independent and could be blocked by anti-SR-A antibodies. The presence of apo A-I and apo E in pathological deposits, such as atherosclerotic lesions and neurotoxic Alzheimer's plaques, suggests a possible contribution of SR-A-dependent adhesion of macrophages to an inflammatory microenvironment.
清道夫受体 A（SR-A）是一种多功能、多配体的模式识别受体，在先天免疫、凋亡细胞清除以及与年龄相关的退行性病理中发挥作用，如动脉粥样硬化和阿尔茨海默病。已知的内源性 SR-A 配体是带负电荷的，包括修饰的脂蛋白、晚期糖基化终产物和细胞外基质蛋白。尚未鉴定出天然的血浆配体，但已知 SR-A 识别未鉴定的血清成分介导整合素非依赖性巨噬细胞黏附，这可能导致慢性局部炎症。在这项研究中，我们使用高通量分级和筛选方法来鉴定可能介导巨噬细胞黏附的新型内源性 SR-A 配体。发现 SR-A 分别以游离脂质和结合脂质的形式识别可交换载脂蛋白 A-I 和 E（分别为 apo A-I 和 apo E），这表明共享的两亲性α-螺旋可能是潜在的识别基序。RAW 264.7 巨噬细胞黏附到涂有 apo A-I 和 apo E4 的表面是整合素非依赖性的，可以被抗 SR-A 抗体阻断。apo A-I 和 apo E 存在于动脉粥样硬化病变和神经毒性阿尔茨海默病斑块等病理沉积物中，表明 SR-A 依赖性巨噬细胞黏附可能对炎症微环境有一定的贡献。
