Moore Kathryn J, El Khoury Joseph, Medeiros Lea A, Terada Kinya, Geula Changiz, Luster Andrew D, Freeman Mason W
Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
J Biol Chem. 2002 Dec 6;277(49):47373-9. doi: 10.1074/jbc.M208788200. Epub 2002 Sep 17.
beta-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer's disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. The class B scavenger receptor, CD36, mediates binding of fibrillar beta-amyloid to cells of the monocyte/macrophage lineage, including brain macrophages (microglia). In this study, we demonstrate that in microglia and other tissue macrophages, beta-amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42. Interruption of this signaling cascade, through targeted disruption of Src kinases downstream of CD36, inhibits macrophage inflammatory responses to beta-amyloid, including reactive oxygen and chemokine production, and results in decreased recruitment of microglia to sites of amyloid deposition in vivo. The finding that engagement of CD36 by beta-amyloid initiates a Src kinase-dependent production of inflammatory mediators in cells of the macrophage lineage reveals a novel receptor-mediated pro-inflammatory signaling pathway of potential therapeutic importance.
β-淀粉样蛋白的积累与阿尔茨海默病患者大脑中的病理变化相关，最近在另一种慢性炎症性疾病动脉粥样硬化的斑块中也被发现。B类清道夫受体CD36介导纤维状β-淀粉样蛋白与单核细胞/巨噬细胞谱系细胞（包括脑巨噬细胞（小胶质细胞））的结合。在本研究中，我们证明，在小胶质细胞和其他组织巨噬细胞中，β-淀粉样蛋白启动了一个依赖CD36的信号级联反应，该反应涉及Src激酶家族成员Lyn和Fyn以及丝裂原活化蛋白激酶p44/42。通过靶向破坏CD36下游的Src激酶来中断这一信号级联反应，可抑制巨噬细胞对β-淀粉样蛋白的炎症反应，包括活性氧和趋化因子的产生，并导致体内小胶质细胞向淀粉样蛋白沉积部位的募集减少。β-淀粉样蛋白与CD36的结合在巨噬细胞谱系细胞中启动Src激酶依赖性炎症介质的产生，这一发现揭示了一条具有潜在治疗重要性的新型受体介导的促炎信号通路。
