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Roles of microglial purinergic receptors in inflammatory conditions of the brain.

机译：小神经胶质嘌呤能受体在脑部炎症中的作用。

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摘要

Microglia, the resident immune cells of brain, mediate inflammatory responses leading to progressive neuronal damage in neurodegenerative diseases. Binding of ATP to purinergic receptors activates microglia thereby inducing cellular responses in inflamed brain cells. The two families of purinergic receptors, labelled P2XR (ionotropic) and P2YR (metabotropic) contribute to inflammatory responses in microglia. The first two parts of my study focused on the involvement and role of the ionotropic purinergic receptor, P2X7R in mediating inflammatory responses such as secretion of pro-inflammatory factors in vitro and in vivo. The final part of my study concentrated on purinergic receptor-dependent intracellular Ca2+ ([Ca2+]i) mobilization and functional responses in human fetal microglia.; A detailed in vivo study was carried out on the involvement of P2X7R in mediating lipopolysaccharide (LPS)-induced inflammatory responses and neuronal damage in rat striatum. LPS-injected striatum exhibited a marked increase in the expression and production of P2X7R compared with control (saline)-injected animals. Additionally, LPS injection upregulated a host of pro-inflammatory mediators and reduced neuronal viability. The P2X 7R antagonist, oxidized ATP (oxATP) was effective in attenuating expressions of all inflammatory mediators; most importantly oxATP was protective for striatal neurons. In vitro, I found LPS stimulation of cultured human microglia enhanced cellular expressions of inflammatory mediators and increased [C2+]i mobilization which were blocked with oxATP treatment. Overall, the results from this work indicate that P2X7R plays a critical role in LPS-induced inflammatory responses including induction of neuronal damage.; Subsequently a series of studies was designed to examine putative roles of P2X7R in mediating inflammatory responses with relevance to the pathology typical of Alzheimer's disease (AD). First, I found microglia isolated from AD brains expressed enhanced P2X7R compared with microglia obtained from non-demented individuals. In a second study, human fetal microglia stimulated with Abeta1-42 peptide exhibited markedly elevated levels of P2X7R compared with untreated cells. Also, P2X 7R-mediated Ca2+ responses were increased with Abeta 1-42 pretreatment of cells relative to untreated cells. Finally, in vivo double immunostaining analysis showed considerable P2X 7R co-localized with microglia following injection of Abeta1-42 into rat hippocampus. The overall results from this section of study show the involvement of P2X7R in mediating microglial purinergic inflammatory responses in AD brain.; We were also interested in the contribution of purinergic receptors other than P2X7R in mediating inflammatory responses. I focused on cyclooxygenase-2 (COX-2) since this enzyme is highly elevated in inflamed brain and contributes to inflammation-induced cytotoxicity. In this research, we used a low concentration of ATP (100 muM) to eliminate contributions of P2X7R since activation of this purinergic subtype receptor requires concentrations of ATP in excess of 1mM. In summary, we found that the block of P2XR (candidate P2X4R) increased the duration of ATP-mediated [Ca2+] i responses and upregulated expression and production of COX-2. The prolonged response involved influx of Ca2+ through store-operated channels (SOC) and was suggested as a consequence of removal of cell depolarization by the block of P2XR. Inhibition of SOC was then shown to be effective in attenuating COX-2 expression in human microglia. These novel results link inhibition of P2XR, other than P2X7R, with upregulation of COX-2 in human microglia with the link involving SOC-mediated Ca2+ influx.; The overall findings from this study suggest that pharmacological manipulation of P2X7R and other purinergic receptors could serve as a potential therapeutic intervention in modulating inflammatory responses in microglia.
机译：小胶质细胞是大脑的固有免疫细胞，介导炎症反应，导致神经退行性疾病中进行性神经元损伤。 ATP与嘌呤能受体结合会激活小胶质细胞，从而在发炎的脑细胞中诱导细胞反应。嘌呤能受体的两个家族，标记为P2XR（离子性）和P2YR（代谢性），有助于小胶质细胞的炎症反应。我的研究的前两部分着眼于离子型嘌呤能受体P2X7R在介导炎症反应（例如体内和体外促炎因子分泌）中的参与和作用。我研究的最后一部分集中在人胎儿小胶质细胞中嘌呤能受体依赖性细胞内Ca2 +（[Ca2 +] i）的动员和功能反应。对P2X7R参与介导脂多糖（LPS）诱导的大鼠纹状体炎症反应和神经元损伤进行了详细的体内研究。与注射对照（盐水）的动物相比，注射LPS的纹状体在P2X7R的表达和产生中表现出明显的增加。此外，LPS注射上调了许多促炎介质，并降低了神经元的生存能力。 P2X 7R拮抗剂氧化ATP（oxATP）可有效减弱所有炎症介质的表达。最重要的是，oxATP对纹状体神经元具有保护作用。在体外，我发现LPS刺激培养的人小胶质细胞可增强炎症介质的细胞表达并增加[C2 +] i动员，而这被oxATP处理阻止。总体而言，这项工作的结果表明P2X7R在LPS诱导的炎症反应（包括诱导神经元损伤）中起关键作用。随后，设计了一系列研究，以检验P2X7R在介导炎症反应中与阿尔茨海默病（AD）典型病理学相关的推定作用。首先，我发现从AD大脑中分离出的小胶质细胞与从非痴呆症个体获得的小胶质细胞相比，P2X7R增强。在第二项研究中，与未经处理的细胞相比，用Abeta1-42肽刺激的人胎儿小胶质细胞显示P2X7R的水平显着升高。而且，相对于未处理的细胞，Abeta 1-42预处理的细胞增加了P2X 7R介导的Ca2 +响应。最后，体内双重免疫染色分析显示，在将Abeta1-42注射入大鼠海马体后，大量P2X 7R与小胶质细胞共定位。该研究部分的总体结果表明，P2X7R参与了AD脑中小胶质嘌呤能级炎症反应的介导。我们还对除P2X7R以外的嘌呤能受体在介导炎症反应中的作用感兴趣。我专注于环氧合酶2（COX-2），因为该酶在发炎的大脑中高度升高，并有助于炎症诱导的细胞毒性。在这项研究中，我们使用了低浓度的ATP（100μM）来消除P2X7R的贡献，因为激活该嘌呤能亚型受体需要的ATP浓度超过1mM。总之，我们发现P2XR（候选P2X4R）的阻滞增加了ATP介导的[Ca2 +] i反应的持续时间，并上调了COX-2的表达和产生。延长的反应包括通过存储操作通道（SOC）流入Ca2 +，这是由于P2XR阻滞消除了细胞去极化作用的结果。研究表明，抑制SOC可有效减弱人小胶质细胞中COX-2的表达。这些新颖的结果将人小胶质细胞中COX-2的上调与除P2X7R以外的P2XR抑制联系在一起，并涉及SOC介导的Ca2 +内流。这项研究的总体发现表明，P2X7R和其他嘌呤能受体的药理学操纵可作为调节小胶质细胞炎症反应的潜在治疗手段。

著录项

  • 作者

    Choi, Hyun Beom.;

  • 作者单位

    The University of British Columbia (Canada).;

  • 授予单位 The University of British Columbia (Canada).;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 165 p.
  • 总页数 165
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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