Complement component, neuroinflammation and depression

补体成分、神经炎症和抑郁症

• 批准号: 9914544
• 负责人: Anilkumar Pillai
• 金额: $ 38.71万
• 依托单位: AUGUSTA UNIVERSITY
• 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/9914544
• 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 Monitoring; 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/antagonist; macrophage; mental health related disorder; 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.

越来越多的证据表明，免疫系统在糖尿病的病理生理学中起着重要作用。 抑郁症。作为引发抑郁症的一个基本因素，慢性应激与 免疫失调和随后的炎症。而抗炎药已经被测试为 抗抑郁药，在抑郁症受试者的子集上取得了一些成功，针对的是更特定的免疫系统 该机制具有更大的应答率，适用于更广泛的患者。补语 系统是免疫的先天手臂的一部分。补体成分3(C3)，即 补体激活通路在神经炎症中起着关键作用。小胶质细胞，主要的免疫 负责免疫监视和神经保护的大脑效应器，使用C3途径进行调节 突触发育。我们最近的研究发现，C3在大鼠前额叶皮质(PFC)的表达增加 抑郁症自杀(DS)受试者和抑郁症的小鼠模型(慢性不可预测应激，CUS)。C3 信号转导是通过其受体C3a受体1(C3aR1)进行的。小胶质细胞和 单核/巨噬细胞(Mo/MFS)表达C3aR1。尽管我们的研究显示慢性压力的减弱- 在C3aR1基因敲除小鼠中诱导抑郁样行为，这些发现没有区分C3aR1在 小胶质细胞和Mo/MFS。我们假设小胶质细胞C3激活介导慢性应激诱导 抑郁样行为和神经炎症的增加。为了支持这一点，我们的出版和初步 研究发现，C3在电离钙结合受体分子1+细胞(Iba1)中高表达。 代表内源性小胶质细胞和潜在的浸润性脑巨噬细胞)。此外，还增加了 DS患者PFC中Iba1+细胞表达C3；(2)核因子-kappaB的抑制作用 (NFκB；抑郁症相关的关键炎症调节因子)信号传递减弱CUS诱导的血管内皮细胞 小鼠PFC中C3蛋白水平。这与之前报道的C3启动子包含两个 推测的核因子κB结合部位和C3是直接的核因子κB靶标；和(3)小胶质细胞显著减少 减轻CUS诱导的小鼠C3升高、单核细胞浸润和抑郁样行为。而当 这些观察结果令人振奋，提出了几个关键问题。小胶质细胞中是否存在核因子κB信号 介导慢性应激诱导的C3表达增加？小胶质细胞C3aR1是否介导应激- 诱导的抑郁样行为和神经炎症 ？ C3表达的增加是否与 与抑郁症患者PFC中小胶质细胞活化和单核细胞浸润有关，并与 是抑郁还是自杀？为了解决这些问题，我们将1)调查慢性萎缩性胃炎 应激诱导C3表达增加；2)确定小胶质细胞C3aR1缺乏是否减弱CUS- 诱导的单核细胞募集、神经炎症和抑郁样行为；以及3)量化 抑郁症患者PFC中C3、小胶质细胞活化与单核细胞浸润的关系