Microglia, Complement, and Pain

小胶质细胞、补体和疼痛

• 批准号: 7903813
• 负责人: CLIFFORD J WOOLF
• 金额: $ 3.44万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903813
• 关键词: Afferent Neurons; Anaphylatoxins; Apoptosis; Attenuated; Behavior; Binding; C5a anaphylatoxin receptor; CCL2 gene; CCL3 gene; CCL8 gene; CX3CL1 gene; Calcium; Cessation of life; Complement; Complement 5a; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Excision; Face; Feedback; Fractalkine; Gene Activation; Genes; Hypersensitivity; IL6 gene; ITGAM gene; Immune; Immune response; Immunologics; In Vitro; Inflammation; Injury; Interferon Type II; Knockout Mice; Lead; Macrophage Inflammatory Protein-1; Membrane; Microglia; Modeling; Molecular Profiling; Monocyte Chemoattractant Protein-1; Mus; Mutant Strains Mice; Nature; Nerve; Nervous system structure; Neuraxis; Neuroglia; Neurons; Pain; Pathway interactions; Peripheral; Peripheral nerve injury; Posterior Horn Cells; Predisposition; Production; Rattus; Relative (related person); Research Personnel; Rodent; Role; Signal Transduction; Signaling Molecule; Spinal Cord; Stimulus; Structure of trigeminal nerve spinal tract nucleus; Synaptic Transmission; Testing; base; chemokine; complement C5b; complement pathway; cytokine; dorsal horn; gene induction; in vivo; inflammatory neuropathic pain; inhibitor/antagonist; injured; macrophage; monocyte chemoattractant protein-2; nerve injury; neutralizing antibody; novel; null mutation; pain behavior; painful neuropathy; programs; receptor; research study; treatment strategy

DESCRIPTION (provided by applicant): Peripheral neuropathic pain arises from diverse changes in the peripheral and central nervous systems that include a reciprocal interaction between the immune and nervous systems. We find from a microarray expression profile analysis that immunologic gene activation in microglia in the dorsal horn is a major common feature of rodent peripheral neuropathic pain models and includes most prominently a local induction of components of the complement cascade in the spinal cord. Blocking the complement cascade by depleting its components in rat spinal cord or in mutant mice reduces, moreover, pain hypersensitivity in neuropathic pain models. Based on this, we hypothesize that peripheral nerve injury results in production by injured sensory neurons of a signal that is transported to the central terminals of the afferents in the dorsal horn/spinal nucleus of the trigeminal where it acts on microglia to induce complement genes. Activation of the classical complement cascade pathway locally in the superficial dorsal horn results in production of C5a anaphylatoxin and assembly of the membrane attack complex (MAC). C5a, we hypothesize, acts via the C5a receptor to alter microglial and neuronal function, while MAC, we propose, is specifically assembled on those neurons that do not express CD59, an endogenous inhibitor of MAC assembly, and by increasing calcium influx in the neurons, increases their excitability and vulnerability to apoptosis. To test this hypothesis we propose to determine: 1) Which peripheral stimuli; activity, inflammation or axonal damage, induce complement genes in microglia in the dorsal horn 2) Which cytokines and chemokines induce complement genes in microglia, 3) The role of the complement cascade in producing neuropathic pain and specifically whether C5a or assembly of the MAC is the prime effector of the pain, and 4) If complement activation alters excitability in dorsal horn neurons sufficiently to produce excitotoxic apoptosis. We will use this information to devise and test novel treatment strategies for somatic and facial neuropathic pain based either on blocking complement gene induction in microglia or complement cascade activation in the nervous system.

描述（由申请人提供）：外周神经性疼痛由外周和中枢神经系统的各种变化引起，包括免疫系统和神经系统之间的相互作用。我们发现，从微阵列表达谱分析，免疫基因激活小胶质细胞在背角是一个主要的共同特点，啮齿动物周围神经性疼痛模型，最突出的是包括一个局部诱导的补体级联的组成部分在脊髓。此外，通过消耗大鼠脊髓或突变小鼠中的补体级联反应的组分来阻断补体级联反应可降低神经性疼痛模型中的疼痛超敏性。基于此，我们假设周围神经损伤导致由受损的感觉神经元产生信号，该信号被运输到三叉神经背角/脊核中的传入神经的中央末梢，在那里它作用于小胶质细胞以诱导补体基因。在浅表背角局部激活经典补体级联途径导致C5 a过敏毒素的产生和膜攻击复合物（MAC）的组装。我们假设，C5 a通过C5 a受体改变小胶质细胞和神经元功能，而MAC，我们提出，是专门组装在那些不表达CD 59的神经元上，CD 59是MAC组装的内源性抑制剂，并通过增加神经元中的钙内流，增加其兴奋性和对凋亡的脆弱性。为了验证这一假设，我们建议确定：1）哪些周边刺激;活动、炎症或轴突损伤，在背角的小胶质细胞中诱导补体基因2）哪些细胞因子和趋化因子在小胶质细胞中诱导补体基因，3）补体级联在产生神经性疼痛中的作用，特别是C5 a或MAC的组装是否是疼痛的主要效应物，和4）如果补体激活改变背角神经元的兴奋性，足以产生兴奋性毒性细胞凋亡。我们将利用这些信息来设计和测试新的治疗策略，基于阻断小胶质细胞中的补体基因诱导或神经系统中的补体级联激活的躯体和面部神经性疼痛。