Complement Component, Neuroinflammation and Depression

补体成分、神经炎症和抑郁症

• 批准号: 10670822
• 负责人: Anilkumar Pillai
• 金额: $ 38.42万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670822
• 关键词: Address; Affect; Agreement; Amygdaloid structure; Anti-Inflammatory Agents; Antibodies; Antidepressive Agents; Astrocytes; Attenuated; Behavior; Binding Sites; Bone Marrow; Brain; Brain region; Calcium Binding; Cell Adhesion Molecules; Cell surface; Cells; Chimera organism; Chronic; Chronic stress; Complement; Complement 3; Complement 3a; Complement Activation; Complement Inactivators; Confounding Factors (Epidemiology); Depressed mood; Development; Disease; Flow Cytometry; Functional disorder; Goals; Health; Hippocampus; Immune; Immune system; Immunity; Immunofluorescence Immunologic; Immunohistochemistry; Immunologic Surveillance; Infiltration; Inflammation; Intervention; Knockout Mice; LoxP-flanked allele; Macrophage; Mediating; Mental Depression; Mental disorders; Messenger RNA; Microglia; Mission; Mus; Myeloid Cells; National Institute of Mental Health; Neurons; Nuclear; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Play; Population; Prefrontal Cortex; Process; Protein Analysis; Proteins; Public Health; Publishing; Recurrence; Reporting; Role; Signal Transduction; Stress; Substance of Abuse; Suicide; Synapses; Testing; Therapeutic; United States National Institutes of Health; arm; attenuation; complement system; cytokine; depressive behavior; depressive symptoms; inhibitor; ionization; monocyte; mouse model; neuroinflammation; neuroprotection; novel; promoter; receptor; recruit; response; success

Accumulating evidence suggest that the immune system plays an important role in the pathophysiology of depression. As a fundamental factor in the provocation of depression, chronic stress is associated with dysregulated immunity and subsequent inflammation. While anti-inflammatory agents have been tested as antidepressants, with some success in a subset of depressed subjects, targeting a more specific immune mechanism could have greater response rate and be applicable to a wider range of patients. The complement system is part of the innate arm of immunity. Complement component 3 (C3), the converging point of the complement activation pathways plays critical roles in neuroinflammation. Microglia, the principal immune effector of the brain responsible for immunosurveillance and neuroprotection, use C3 pathway to regulate synapse development. Our recent study found increased expression of C3 in the prefrontal cortex (PFC) of both depressed suicide (DS) subjects and mouse model (chronic unpredictable stress, CUS) of depression. C3 signaling is mediated through its receptor, C3a receptor 1 (C3aR1). Both microglia and monocytes/macrophages (Mo/MFs) express C3aR1. Although our study showed attenuation of chronic stress- induced depressive-like behavior in C3aR1 knockout mice, these findings do not distinguish between C3aR1 in microglia and Mo/MFs. We hypothesize that microglial C3 activation mediates chronic stress-induced increases in depressive-like behavior and neuroinflammation. In supporting this, our published and preliminary studies found that C3 is highly expressed in Ionized calcium binding adaptor molecule1+ cells (Iba1, which represent endogenous microglia and potentially infiltrating brain macrophages) following CUS. Also, increased expression of C3 was found in in Iba1+ cells of PFC of DS subjects; (2) Inhibition of nuclear factor-kappa B (NFκB; a key regulator of inflammation implicated in depression) signaling attenuated CUS-induced increase in C3 protein levels in mouse PFC. This is in agreement with previous reports that C3 promoter contains two putative NFκB binding sites and C3 is a direct NFκB target; and (3) Depletion of microglia significantly attenuated CUS-induced C3 elevation, infiltration of monocytes and depressive-like behavior in mice. While these observations are exciting, several critical questions are raised. Whether NFκB signaling in microglia mediates chronic stress-induced increase in C3 expression? Whether microglial C3aR1 mediates stress- induced depressive-like behavior and neuroinflammation ? Whether increases in C3 expression are associated with microglia activation and monocyte infiltration in the PFC of depressed subjects, and are primarily related to depression or suicide? To address these questions, we will 1) investigate mechanisms by which chronic stress induces increases in C3 expression; 2) determine whether microglial C3aR1 deficiency attenuates CUS- induced monocyte recruitment, neuroinflammation and depressive-like behavior; and 3) quantify the relationship between C3, microglia activation, and monocyte infiltration in the PFC of depressed subjects.

积累的证据表明，免疫系统在病理生理中起重要作用 沮丧。作为抑郁症的基本因素，慢性压力与 免疫学和随后的炎症失调。虽然已经测试了抗炎剂 抗抑郁药，在抑郁受试者的一部分中取得了一定的成功，针对更具体的免疫 机制可能具有更高的缓解率，并且适用于更广泛的患者。完成 系统是免疫先天部门的一部分。补体组件3（C3），融合点 补体激活途径在神经炎症中起关键作用。小胶质细胞，主要免疫 负责免疫监视和神经保护的大脑的效应因子，使用C3途径调节 突触发展。我们最近的研究发现C3在前额叶皮层（PFC）中的表达增加 抑郁症的自杀（DS）和小鼠模型（慢性不可预测的压力，CUS）均抑郁症。 C3 信号通过其受体C3A受体1（C3AR1）介导。小胶质细胞和 单核细胞/巨噬细胞（MO/MFS）表达C3AR1。尽管我们的研究表明慢性应激的衰减 在C3AR1敲除小鼠中诱导的抑郁样行为，这些发现没有区分C3AR1 小胶质细胞和mo/mfs。我们假设小胶质细胞C3激活介导了慢性应激诱导的 抑郁样行为和神经炎症的增加。在支持这一点时，我们出版和初步 研究发现，C3在离子化的钙衔接衔接子分子1+细胞中高度表达（IBA1，哪个 CUS表示内源性小胶质细胞和潜在浸润的脑巨噬细胞）。另外，增加 在DS受试者的PFC的IBA1+细胞中发现了C3的表达。 （2）抑制核因子-kappa b （NFκB；与抑郁有关的炎症的关键调节剂）信号传导减弱了CUS诱导的增加 小鼠PFC中的C3蛋白水平。这与以前的报道一致，即C3启动子包含两个 推定的NFκB结合位点和C3是直接的NFκB靶标。 （3）小胶质细胞的耗竭 减弱的CUS诱导的C3升高，单核细胞的浸润和小鼠的抑郁样行为。尽管 这些观察令人兴奋，提出了一些关键问题。小胶质细胞中的NFκB是否信号传导 介导慢性应激引起的C3表达增加？小胶质细胞C3AR1是否介导应力 - 诱导的抑郁样行为和神经炎症 ？ C3表达的增加是否相关 抑郁受试者的PFC中的小胶质细胞激活和单核细胞浸润，主要是相关的 抑郁还是自杀？为了解决这些问题，我们将1）调查慢性的机制 应力诱导C3表达增加。 2）确定小胶质细胞C3AR1缺乏是否会减弱cus- 诱导的单核细胞募集，神经炎症和抑郁样行为； 3）量化 抑郁受试者的PFC中C3，小胶质细胞激活和单核细胞浸润之间的关系。