Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism
Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism
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DOI：
10.1523/jneurosci.2557-04.2004
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发表时间：
2004-11-03
影响因子：
5.3
通讯作者：
Landreth, G
中科院分区：
文献类型：
--
作者：
Koenigsknecht, J;Landreth, G
小胶质细胞是中枢神经系统中主要的免疫效应细胞和吞噬细胞。这些细胞与阿尔茨海默病（AD）患者大脑中发现的含有纤维β -淀粉样蛋白（fAbeta）的斑块有关。斑块相关的小胶质细胞经历表型转化为活化表型，并负责局灶性炎症反应的发展，从而加剧和加速疾病进程。矛盾的是，尽管阿尔茨海默病患者的大脑中存在大量活化的小胶质细胞，但这些细胞不能对Abeta沉积物产生吞噬反应，但在体外可以有效地吞噬Abeta原纤维和斑块。我们报道小胶质细胞在体外暴露于fAbeta诱导吞噬的机制不同于经典吞噬受体、Ig受体（FcRgammaI和FcgammaRIII）或补体受体。小胶质细胞通过最近发现的Abeta细胞表面受体复合物与fAbeta相互作用，该复合物包括b类清除率受体CD36、α (6) β(1)整合素和CD47（整合素相关蛋白）。受体复合物的每个组分特异性拮抗剂阻断fabeta刺激的吞噬作用。这些数据表明，这些受体集合的参与是诱导吞噬作用所必需的。这种受体复合物刺激的吞噬反应主要由β(1)整合素相关过程驱动，该过程在形态和机制上与经典的I型和II型吞噬机制不同。这些数据为通过受体介导的非经典吞噬机制吞噬fAbeta提供了证据。
Microglia are the principle immune effector and phagocytic cells in the CNS. These cells are associated with fibrillar beta-amyloid (fAbeta)-containing plaques found in the brains of Alzheimer's disease ( AD) patients. The plaque-associated microglia undergo a phenotypic conversion into an activated phenotype and are responsible for the development of a focal inflammatory response that exacerbates and accelerates the disease process. Paradoxically, despite the presence of abundant activated microglia in the brain of AD patients, these cells fail to mount a phagocytic response to Abeta deposits but can efficiently phagocytose Abeta fibrils and plaques in vitro.We report that exposure of microglia to fAbeta in vitro induces phagocytosis through mechanisms distinct from those used by the classical phagocytic receptors, the Ig receptors (FcRgammaI and FcgammaRIII) or complement receptors. Microglia interact with fAbeta through a recently characterized Abeta cell surface receptor complex comprising the B-class scavenger receptor CD36, alpha(6)beta(1) integrin, and CD47 (integrin-associated protein). Antagonists specific for each component of the receptor complex blocks fAbeta-stimulated phagocytosis. These data demonstrated that engagement of this ensemble of receptors is required for induction of phagocytosis. The phagocytic response stimulated by this receptor complex is driven principally by a beta(1) integrin-linked process that is morphologically and mechanistically distinct from the classical type I and type II phagocytic mechanisms. These data provide evidence for phagocytic uptake of fAbeta through a receptor-mediated, nonclassical phagocytic mechanism.