Activation of toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid β peptide
Activation of toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid β peptide
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DOI：
10.1074/jbc.m508125200
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发表时间：
2006-02-10
影响因子：
4.8
通讯作者：
Wang, JM
中科院分区：
文献类型：
--
作者：
Chen, KQ;Iribarren, P;Wang, JM
人 G 蛋白偶联甲酰肽受体样 1 (FPRL1) 及其小鼠同源物 mFPR2 介导与炎症和细菌感染相关的多种多肽的趋化活性，包括 42 个氨基酸形式的淀粉样蛋白 β 肽 (A beta(42))，这是阿尔茨海默病的致病因子。由于 mFPR2 在小鼠小胶质细胞中可被促炎刺激物诱导，例如细菌脂多糖（Toll 样受体 4 (TLR4) 的配体），因此我们研究了 TLR2 在 mFPR2 调节中的作用。我们发现，源自革兰氏阳性菌金黄色葡萄球菌的 TLR2 激动剂肽聚糖 (PGN) 可在小鼠小胶质细胞系和原代小胶质细胞中诱导大量 mFpr2 mRNA 表达。这与细胞响应 mFPR2 激动剂肽的趋化性显着增加有关。此外，TLR2 的激活显着增强了 mFPR2 介导的小胶质细胞对 A beta(42) 的摄取。机制基础研究表明，PGN 激活 MAPK 和 I kappa Ba，PGN 对 mFPR2 诱导的作用依赖于通过 ERK1/2 和 p38 MAPK 的信号通路。 PGN 在小胶质细胞上使用 TLR2 的事实是，用靶向小鼠 TLR2 的短干扰 RNA 转染的 N9 细胞在 PGN 刺激后未能显示出功能性 mFPR2 表达增加。我们的结果表明，TLR2 在小胶质细胞中具有潜在的重要作用，可以促进细胞对大脑炎症和神经退行性疾病病变中产生的化学引诱剂的反应。
The human G-protein-coupled formyl peptide receptor-like 1 (FPRL1) and its mouse homologue mFPR2 mediate the chemotactic activity of a variety of polypeptides associated with inflammation and bacterial infection, including the 42-amino acid form of amyloid beta peptide (A beta(42)), a pathogenic factor in Alzheimer disease. Because mFPR2 was inducible in mouse microglial cells by proinflammatory stimulants, such as bacterial lipopolysaccharide, a ligand for the Toll-like receptor 4 (TLR4), we investigated the role of TLR2 in the regulation of mFPR2. We found that a TLR2 agonist, peptidoglycan (PGN) derived from Gram-positive bacterium Staphylococcus aureus, induced considerable mFpr2 mRNA expression in a mouse microglial cell line and primary microglial cells. This was associated with a markedly increased chemotaxis of the cells in response to mFPR2 agonist peptides. In addition, activation of TLR2 markedly enhanced mFPR2-mediated uptake of A beta(42) by microglia. Studies of the mechanistic basis showed that PGN activates MAPK and I kappa Ba, and the effect of PGN on induction of mFPR2 was dependent on signaling pathways via ERK1/2 and p38 MAPKs. The use of TLR2 on microglial cells by PGN was supported by the fact that N9 cells transfected with short interfering RNA targeting mouse TLR2 failed to show increased expression of functional mFPR2 after stimulation with PGN. Our results demonstrated a potentially important role for TLR2 in microglial cells of promoting cell responses to chemoattractants produced in lesions of inflammatory and neurodegenerative diseases in the brain.