Complement Component, Neuroinflammation and Depression

越来越多的证据表明，免疫系统在免疫系统疾病的病理生理学中起着重要作用。 萧条作为引发抑郁症的一个基本因素，慢性压力与以下因素有关： 免疫失调和随后的炎症。虽然抗炎剂已被测试为 抗抑郁药，在一部分抑郁症受试者中取得了一些成功，靶向更特异的免疫系统， 机制可能具有更高的响应率，适用于更广泛的患者。补体 免疫系统是免疫系统的一部分。补体成分3（C3），补体的会聚点， 补体激活途径在神经炎症中起关键作用。小胶质细胞，主要的免疫细胞 负责免疫监视和神经保护的脑效应器，使用C3通路调节 突触发育我们最近的一项研究发现，C3在前额叶皮层（PFC）的表达增加， 抑郁自杀（DS）受试者和抑郁的小鼠模型（慢性不可预测的压力，CUS）。C3 信号传导通过其受体C3 a受体1（C3 aR 1）介导。小胶质细胞和 单核细胞/巨噬细胞（Mo/MF）表达C3 aR 1。尽管我们的研究表明慢性压力会减弱- 在C3 aR 1基因敲除小鼠中诱导抑郁样行为，这些发现并不能区分C3 aR 1与 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的 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在离子化的钙结合衔接分子1+细胞中高度表达（Iba 1， 代表内源性小胶质细胞和潜在的浸润性脑巨噬细胞）。此外，增加 （2）核因子-κ B的抑制 (NFκB;一种与抑郁症有关的炎症关键调节因子）信号转导减弱了β-淀粉样蛋白诱导的 这与先前报道的C3启动子含有两个 推测的NFκB结合位点和C3是直接的NFκB靶点;和（3）小胶质细胞的显著消耗 减弱了C3升高、单核细胞浸润和小鼠抑郁样行为。而 这些观察结果令人兴奋，但也提出了几个关键问题。小胶质细胞中NFκB信号是否 介导慢性应激诱导的C3表达增加？小胶质细胞C3 aR 1是否介导应激- 诱导抑郁样行为和神经炎症 ? C3表达增加是否与 与抑郁症患者PFC中的小胶质细胞活化和单核细胞浸润有关， 抑郁症或自杀为了解决这些问题，我们将1）研究慢性炎症的机制， 应激诱导C3表达增加; 2）确定小胶质细胞C3 aR 1缺陷是否会减弱CUS- 诱导的单核细胞募集、神经炎症和抑郁样行为;以及3）定量 抑郁症患者PFC中C3、小胶质细胞活化和单核细胞浸润之间的关系

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.