Complement Component, Neuroinflammation and Depression

补体成分、神经炎症和抑郁症

基本信息

批准号：
10462803
负责人：
Anilkumar Pillai
金额：
$ 38.7万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
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/10462803
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 Calcium ion 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 Hippocampus (Brain)Immune Immune system Immunity Immunofluorescence Immunologic Immunohistochemistry Immunologic Surveillance Infiltration Inflammation Intervention Knockout Mice LoxP-flanked allele Mediating Mental Depression Messenger RNA Microglia Mission Mus Myeloid Cells NF-kappa B National Institute of Mental Health Neurons Pathway interactions Patients Peripheral Pharmaceutical Preparations Play Population Prefrontal Cortex Process Protein Analysis Proteins Public Health Publishing Reporting Role Signal Transduction Stress Substance of Abuse Suicide Synapses Testing Therapeutic United States National Institutes of Health arm attenuation base complement system cytokine depressive behavior depressive symptoms inhibitor macrophage mental health related disorder monocyte mouse model neuroinflammation neuroprotection novel promoter receptor recruit response success

项目摘要

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.

越来越多的证据表明，免疫系统在疾病的病理生理学中发挥着重要作用。作为引发抑郁症的一个基本因素，慢性压力与抑郁症有关。免疫失调和随后的炎症已被测试为。抗抑郁药，在部分抑郁症受试者中取得了一些成功，针对更特异性的免疫该机制可以具有更高的反应率并适用于更广泛的患者。系统是先天免疫臂的一部分，是补体成分 3 (C3) 的汇聚点。激活途径在神经炎症补体（主要免疫系统）中发挥着关键作用。负责免疫监视和神经保护的大脑效应器，利用C3途径进行调节我们最近的研究发现 C3 在前额皮质 (PFC) 中的表达增加。抑郁症自杀（DS）受试者和抑郁症小鼠模型（慢性不可预测压力，CUS）。信号传导通过其受体 C3a 受体 1 (C3aR1) 介导。单核细胞/巨噬细胞 (Mo/MF) 表达 C3aR1，尽管我们的研究显示慢性应激的减弱。在 C3aR1 敲除小鼠中诱导抑郁样行为，这些发现并不能区分 C3aR1 我们发现小胶质细胞 C3 激活介导慢性应激诱导。为了支持这一点，我们发表了初步的研究。研究发现，C3 在离子钙结合接头分子 1+ 细胞（Iba1，其中 CUS 后内源性小胶质细胞和潜在浸润的脑巨噬细胞也增加。 DS受试者PFC Iba1+细胞中发现C3表达；（2）核因子-κB的抑制；（NFκB；与抑郁症有关的炎症的关键调节因子）信号减弱了 CUS 诱导的小鼠 PFC 中的 C3 蛋白水平这与之前的报道一致，即 C3 启动子包含两个。推定的 NFκB 结合位点，C3 是 NFκB 的直接靶标；(3) 小胶质细胞显着减少；减轻 CUS 诱导的 C3 升高、单核细胞浸润和小鼠抑郁样行为。这些观察结果令人兴奋，并提出了小胶质细胞中是否存在 NFκB 信号传导的几个关键问题。介导慢性应激诱导的 C3 表达增加？诱发抑郁样行为和神经炎症？ C3 表达增加是否相关与抑郁症受试者 PFC 中的小胶质细胞激活和单核细胞浸润有关，并且主要相关为了解决这些问题，我们将 1) 研究慢性疾病的机制应激诱导 C3 表达增加；2) 确定小胶质细胞 C3aR1 缺乏是否会减弱 CUS- 诱导单核细胞募集、神经炎症和抑郁样行为；3) 量化抑郁症受试者 PFC 中 C3、小胶质细胞激活和单核细胞浸润之间的关系。