TLR2 Is a Primary Receptor for Alzheimer's Amyloid β Peptide To Trigger Neuroinflammatory Activation
TLR2 Is a Primary Receptor for Alzheimer's Amyloid β Peptide To Trigger Neuroinflammatory Activation
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DOI：
10.4049/jimmunol.1101121
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发表时间：
2012-02-01
影响因子：
4.4
通讯作者：
Fassbender, Klaus
中科院分区：
文献类型：
--
作者：
Liu, Shirong;Liu, Yang;Fassbender, Klaus
细胞外沉积的淀粉样β肽（Aβ）激活的小胶质细胞在阿尔茨海默病的发病机制中扮演着一把双刃剑的角色：一方面，它们通过释放神经毒性促炎介质（M1激活）来损害神经元；另一方面，它们通过释放神经毒性促炎介质（M1激活）来损害神经元。另一方面，它们通过触发抗炎/神经营养性 M2 激活以及通过吞噬作用清除 Aβ 来保护神经元。 TLRs 与 Aβ 诱导的小胶质细胞炎症激活和 Aβ 内化有关，但其机制仍不清楚。在这项研究中，我们使用实时表面等离振子共振光谱和传统的生化下拉分析来证明 TLR2 和人 A beta (A beta 42) 的 42-aa 聚集形式之间的直接相互作用。 TLR2 缺陷减少了 Aβ 42 触发的炎症激活，但增强了培养的小胶质细胞和巨噬细胞中的 Aβ 吞噬作用。通过在不内源表达 TLR2 的 HEK293 细胞中表达 TLR2，我们观察到 TLR2 表达使 HEK293 细胞能够对 A beta 42 做出反应。通过 tlr2 基因的定点诱变，我们确定氨基酸 EKKA (741-744) 是炎症信号转导的关键细胞质结构域。通过在TLR2转基因HEK293细胞中共表达TLR1或TLR6或在RAW264.7巨噬细胞中沉默tlrs基因，我们观察到TLR2介导的Ab42触发的炎症激活被TLR1增强并被TLR6抑制。使用骨髓嵌合阿尔茨海默病淀粉样蛋白前体转基因小鼠，我们观察到小胶质细胞中 TLR2 的缺乏会导致体内 M1 炎症激活转变为 M2 炎症激活，这与神经元功能的改善有关。我们的研究表明，TLR2 是 Aβ 触发神经炎症激活的主要受体，并表明抑制小胶质细胞中的 TLR2 可能有益于阿尔茨海默病的发病机制。免疫学杂志，2012 年，188：1098-1107。
Microglia activated by extracellularly deposited amyloid beta peptide (A beta) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing A beta via phagocytosis. TLRs are associated with A beta-induced microglial inflammatory activation and A beta internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human A beta (A beta 42). TLR2 deficiency reduced A beta 42-triggered inflammatory activation but enhanced A beta phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to A beta 42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741-744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Ab42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer's amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for A beta to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer's disease pathogenesis. The Journal of Immunology, 2012, 188: 1098-1107.