Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD.
Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD.
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DOI：
10.1186/1742-2094-3-27
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发表时间：
2006-09-27
影响因子：
9.3
通讯作者：
Vitek MP
中科院分区：
文献类型：
--
作者：
Colton CA;Mott RT;Sharpe H;Xu Q;Van Nostrand WE;Vitek MP
小胶质细胞与阿尔茨海默病（AD）中的神经炎斑块相关，并作为大脑中先天免疫反应的主要成分。神经炎斑块是由淀粉样前体蛋白（APP）的淀粉样β肽片段（Abeta）组成的纤维沉积物。大量研究表明，AD中淀粉样蛋白沉积物附近的免疫细胞表达促炎细胞因子的mRNA和蛋白质，从而导致小胶质细胞在AD中表现出经典（Th-1）免疫激活的假设。尽管如此，小胶质细胞激活的复杂作用尚未得到充分探讨，因为最近的研究表明，外周巨噬细胞进入一个“替代”的激活状态。为了研究小胶质细胞的交替激活，我们使用定量RT-PCR来鉴定与小胶质细胞中的交替激活相关的基因，包括在炎症区1（FIZZ 1）中发现的甘露糖受体（MRC 1）和几丁质酶3样3（YM 1）。我们的研究结果证实，用抗炎细胞因子如IL-4和IL-13治疗小胶质细胞诱导了与先前在外周巨噬细胞中观察到的类似的替代激活的典型基因谱。然后，我们使用该基因表达谱来检查两种AD小鼠模型，APPsw（Tg-2576）和Tg-SwDI，分别用于淀粉样蛋白沉积和脑淀粉样蛋白血管病（CAA）的模型。与年龄匹配的对照组相比，Tg-2576小鼠脑中AGI、MRC 1和YM 1 mRNA水平显著增加，而通常与经典激活相关的基因TNFα和NOS 2 mRNA水平分别增加或不变。Tg-SwDI小鼠脑中仅TNFα mRNA增加。在AD患者的大脑样本中也发现了替代激活基因，并与年龄匹配的对照个体进行了比较。在AD脑中，TNFα、AGI、MRC 1和几丁质酶-3样1和2基因（CHI 3L 1; CHI 3L 2）的mRNA显著增加，而NOS 2和IL-1β mRNA无变化。脑内的免疫细胞显示基因谱，其表明从促炎、经典激活状态到参与修复和细胞外基质重塑的替代激活状态的异质性功能表型。我们的数据表明，先天性免疫细胞在AD可能表现出混合激活状态，包括经典和替代激活的特点。
Microglia are associated with neuritic plaques in Alzheimer disease (AD) and serve as a primary component of the innate immune response in the brain. Neuritic plaques are fibrous deposits composed of the amyloid beta-peptide fragments (Abeta) of the amyloid precursor protein (APP). Numerous studies have shown that the immune cells in the vicinity of amyloid deposits in AD express mRNA and proteins for pro-inflammatory cytokines, leading to the hypothesis that microglia demonstrate classical (Th-1) immune activation in AD. Nonetheless, the complex role of microglial activation has yet to be fully explored since recent studies show that peripheral macrophages enter an "alternative" activation state. To study alternative activation of microglia, we used quantitative RT-PCR to identify genes associated with alternative activation in microglia, including arginase I (AGI), mannose receptor (MRC1), found in inflammatory zone 1 (FIZZ1), and chitinase 3-like 3 (YM1). Our findings confirmed that treatment of microglia with anti-inflammatory cytokines such as IL-4 and IL-13 induces a gene profile typical of alternative activation similar to that previously observed in peripheral macrophages. We then used this gene expression profile to examine two mouse models of AD, the APPsw (Tg-2576) and Tg-SwDI, models for amyloid deposition and for cerebral amyloid angiopathy (CAA) respectively. AGI, MRC1 and YM1 mRNA levels were significantly increased in the Tg-2576 mouse brains compared to age-matched controls while TNFα and NOS2 mRNA levels, genes commonly associated with classical activation, increased or did not change, respectively. Only TNFα mRNA increased in the Tg-SwDI mouse brain. Alternative activation genes were also identified in brain samples from individuals with AD and were compared to age-matched control individuals. In AD brain, mRNAs for TNFα, AGI, MRC1 and the chitinase-3 like 1 and 2 genes (CHI3L1; CHI3L2) were significantly increased while NOS2 and IL-1β mRNAs were unchanged. Immune cells within the brain display gene profiles that suggest heterogeneous, functional phenotypes that range from a pro-inflammatory, classical activation state to an alternative activation state involved in repair and extracellular matrix remodeling. Our data suggest that innate immune cells in AD may exhibit a hybrid activation state that includes characteristics of classical and alternative activation.
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影响因子：
4.4
作者：
Gerber, JS;Mosser, DM
通讯作者：
Mosser, DM
影响因子：
4.8
作者：
Davis, J;Xu, F;Van Nostrand, WE
通讯作者：
Van Nostrand, WE
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
4.2
作者：
Benzing, WC;Wujek, JR;Brunden, KR
通讯作者：
Brunden, KR
影响因子：
3.3
作者：
BLASI, E;BARLUZZI, R;BISTONI, F
通讯作者：
BISTONI, F