CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid β-peptide
CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid β-peptide
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DOI：
10.1002/eji.200425585
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发表时间：
2005-03-01
影响因子：
5.4
通讯作者：
Tan, J
中科院分区：
文献类型：
--
作者：
Townsend, KP;Town, T;Tan, J
虽然淀粉样蛋白β-肽（A β）作为A β斑块的沉积涉及小胶质细胞介导的炎症反应的活化，但活化的小胶质细胞最终不能清除阿尔茨海默病（AD）患者或AD小鼠模型脑中的A β斑块。越来越多的证据表明，在A β沉积过程中，慢性小胶质细胞介导的免疫反应通过促进A β斑块形成在病因学上有助于AD发病机制。然而，在大脑A β/β-淀粉样蛋白病理学的背景下，小胶质细胞反应的机制还没有得到很好的理解。我们发现，CD 40与CD 40 L的连接可调节小胶质细胞中A β诱导的先天性免疫反应，包括减少小胶质细胞对外源性A β（1-42）的吞噬作用和增加促炎细胞因子的产生。在A β（1-42）存在下的CD 40连接导致小胶质细胞的适应性激活，如通过增加的MHC II类与A β的共定位所证明的。为了评估它们的抗原呈递细胞（APC）功能，在存在CD 40 L的情况下用A β（1-42）脉冲培养的小胶质细胞，并与CD 4（+）T细胞共培养。在这些条件下，小胶质细胞刺激T细胞衍生的IFN-γ和IL-2产生，表明CD 40信号传导促进APC表型。这些数据为我们以前的工作提供了一个机械的解释。显示当阻断转基因阿尔茨海默氏症小鼠中的CD 40信号传导时，与脑A β/β-淀粉样蛋白病理学减少相关的小胶质细胞增生减少。
Although deposition of amyloid beta-peptide (A beta) as A beta plaques involves activation of microglia-mediated inflammatory responses, activated microglia ultimately fail to clear A beta plaques in the brains of either Alzheimer's disease (AD) patients or AD mouse models. Mounting evidence suggests that chronic microglia-mediated immune response during A beta deposition etiologically contributes to AD pathogenesis by promoting A beta plaque formation. However, the mechanisms that govern microglia response in the context of cerebral A beta/beta-amyloid pathology are not well understood. We show that ligation of CD40 by CD40L modulates A beta-induced innate immune responses in microglia, including decreased microglia phagocytosis of exogenous A beta(1-42) and increased production of pro-inflammatory cytokines. CD40 ligation in the presence of A beta(1-42) leads to adaptive activation of microglia, as evidenced by increased colocalization of MHC class II with A beta. To assess their antigen-presenting cell (APC) function, cultured microglia were pulsed with A beta(1-42) in the presence of CD40L and cocultured with CD4(+) T cells. Under these conditions, microglia stimulate T cell-derived IFN-gamma and IL-2 production, suggesting that CD40 signaling promotes the APC phenotype. These data provide a mechanistic explanation for our previous work. showing decreased microgliosis associated with diminished cerebral A beta/beta-amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice.