Reed-Geaghan Erin G, Savage Julie C, Hise Amy G, Landreth Gary E
Department of Neurosciences, Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Neurosci. 2009 Sep 23;29(38):11982-92. doi: 10.1523/JNEUROSCI.3158-09.2009.
Microglia are the brain's tissue macrophages and are found in an activated state surrounding beta-amyloid plaques in the Alzheimer's disease brain. Microglia interact with fibrillar beta-amyloid (fAbeta) through an ensemble of surface receptors composed of the alpha(6)beta(1) integrin, CD36, CD47, and the class A scavenger receptor. These receptors act in concert to initiate intracellular signaling cascades and phenotypic activation of these cells. However, it is unclear how engagement of this receptor complex is linked to the induction of an activated microglial phenotype. We report that the response of microglial cells to fibrillar forms of Abeta requires the participation of Toll-like receptors (TLRs) and the coreceptor CD14. The response of microglia to fAbeta is reliant upon CD14, which act together with TLR4 and TLR2 to bind fAbeta and to activate intracellular signaling. We find that cells lacking these receptors could not initiate a Src-Vav-Rac signaling cascade leading to reactive oxygen species production and phagocytosis. The fAbeta-mediated activation of p38 MAPK also required CD14, TLR4, and TLR2. Inhibition of p38 abrogated fAbeta-induced reactive oxygen species production and attenuated the induction of phagocytosis. Microglia lacking CD14, TLR4, and TLR2 showed no induction of phosphorylated IkappaBalpha following fAbeta. These data indicate these innate immune receptors function as members of the microglial fAbeta receptor complex and identify the signaling mechanisms whereby they contribute to microglial activation.
小胶质细胞是脑内的组织巨噬细胞，在阿尔茨海默病患者脑内的β-淀粉样蛋白斑块周围呈激活状态。小胶质细胞通过由α(6)β(1)整合素、CD36、CD47和A类清道夫受体组成的表面受体集合与纤维状β-淀粉样蛋白（fAbeta）相互作用。这些受体协同作用，启动细胞内信号级联反应并激活这些细胞的表型。然而，目前尚不清楚该受体复合物的结合如何与激活的小胶质细胞表型的诱导相关联。我们报告，小胶质细胞对fAbeta纤维形式的反应需要Toll样受体（TLR）和共受体CD14的参与。小胶质细胞对fAbeta的反应依赖于CD14，它与TLR4和TLR2共同作用以结合fAbeta并激活细胞内信号传导。我们发现缺乏这些受体的细胞无法启动导致活性氧产生和吞噬作用的Src-Vav-Rac信号级联反应。fAbeta介导的p38丝裂原活化蛋白激酶（MAPK）激活也需要CD14、TLR4和TLR2。抑制p38可消除fAbeta诱导的活性氧产生，并减弱吞噬作用的诱导。缺乏CD14、TLR4和TLR2的小胶质细胞在接触fAbeta后未显示磷酸化IκBα的诱导。这些数据表明这些天然免疫受体作为小胶质细胞fAbeta受体复合物的成员发挥作用，并确定了它们促进小胶质细胞激活的信号传导机制。
