Sex-specific role of CCL5/CCR5 axis in depression and its therapeutic implication

摘要/摘要 严重抑郁障碍(MDD)是一种普遍存在的心理障碍，在中国约有7%的人受到影响 在美国，退伍军人的患病率更高。据估计，大约30%的运营 持久自由(OEF)和伊拉克自由行动(OIF)退伍军人受到抑郁症的影响。有性 抑郁症的二形性是有很好的文献记载的。女性和男性在患病率、症状、 介绍，以及对抗抑郁药物治疗的反应。然而，大多数科学调查 由于实验的限制，主要在男性模型中进行。慢性社会挫败感 应激(CSDS)是研究抑郁症最成熟的模型之一，并且在很大程度上仅限于研究 男性抑郁症。最近，鲁索博士的实验室开发了一种女性CSDS范式，它持续地产生了 在雌性小鼠中表现出类似抑郁的行为，并已被我们的实验室采用。 外周诱导炎性细胞因子有助于抑郁症样行为 在人类和实验模型中。以前，人们发现应激诱导的外周IL-6发挥着 在确定雄性小鼠应激敏感性方面的重要作用。外周炎症的特征 慢性应激综合征雌性小鼠应激敏感性与血浆C- C基序趋化因子配体(CCL5)，但不与IL-6结合。据报道，受试者体内的CCL5水平也较高 与男性相比，女性MDD和外周血CCL5水平更高，牵涉性二型性 CCL5表达与抑郁症的相互作用。基因表达分析显示CCL5受体 应激敏感雌性小鼠大脑前额叶皮质(PFC)中CCR5显著升高 已知在抑郁症中起重要作用，而这种增加在压力敏感的雄性小鼠中没有看到。 与人类MDD RNA-seq数据的交叉检查显示，在女性MDD受试者中，CCR5水平在 腹内侧PFC是对照组的2.8倍，这种增加在 男性MDD受试者，表明人类和小鼠对压力的反应保守。 CCR5是一种七跨膜G蛋白偶联受体，表达于小胶质细胞、星形胶质细胞和 不同脑区的神经元。CCR5的配体激活已被证明可以抑制腺苷环化酶， 激活PI3K/AKT和MAPK信号，改变细胞内钙离子的动员，所有这些都可以影响 突触功能。基于这些观察，我们假设在雌性小鼠中，失败的压力会导致 脑内CCL5的外周增加及其与CCR5的相互作用调节突触可塑性和 促进压力敏感性。我们建议在外围调制CCL5或操纵CCL5/CCR5 PFC中的信号，无论是药理上的还是遗传上的，并使用一系列神经行为测试， 用免疫学和分子技术测试CCL5和CCR5在女性应激敏感性中的作用， 并与雄性小鼠的反应进行比较。我们还将调查应激诱导的神经血管 损伤和相关的血脑屏障渗漏可能促进外周CCL5向脑的渗透。 最后，我们将调查口服FDA批准的CCR5拮抗剂是否对治疗有效 并与抗抑郁药氟西汀进行疗效比较。 我们相信我们的方法将极大地提高我们对潜在的病理生理学的理解。 女性抑郁症并填补了目前关于性别特异性外周和中枢的科学知识的空白 抑郁障碍的潜在机制。申请书中建议的治疗干预措施将 提供即时的板凳到床的翻译，并可能显著改善退伍军人的健康和生活 受压力障碍的影响，包括抑郁症、焦虑症和创伤后应激障碍 (创伤后应激障碍)，尤其与女性退伍军人的健康和福祉有关。

Summary/Abstract Major depressive disorder (MDD) is a widespread psychological disorder affecting ~7% population in the U.S. The prevalence is even higher in veterans. It was estimated that approximately 30% of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans are affected by depression. Sexual dimorphism in depression is well documented. Women and men differ in the prevalence, symptom presentation, and responses to antidepressant treatment. However, the majority of scientific investigations have been predominantly conducted in male models due to experimental limitations. Chronic social defeat stress (CSDS) is one of the best-established models to study depression and has been largely limited to study male depression. Recently, Dr. Russo's lab developed a female CSDS paradigm that consistently produced depression-like behaviors in female mice and has since been adopted in our laboratory. Induction of inflammatory cytokines in the periphery contributes to depression-like behaviors both in humans and in experimental models. Previously, it was found that stress-induced peripheral IL-6 plays an important role in determining stress-susceptibility in male mice. Characterization of peripheral inflammation in female mice following CSDS revealed positive correlation between stress-susceptibility and plasma levels of C- C motif chemokine ligand (CCL5), but not with IL-6. Higher level of CCL5 was also reported in human subjects with MDD and higher levels of peripheral CCL5 in women compared to men, implicating sexual dimorphic interactions between CCL5 expression and depression. Gene expression analysis revealed that CCL5 receptor CCR5 was significantly higher in stress-susceptible female mice in the prefrontal cortex (PFC), a brain region known to play important role in depression, and this increase was not seen in stress-susceptible male mice. Cross-examination with human MDD RNA-seq data showed that in female MDD subjects, the level of CCR5 in the ventromedial PFC was 2.8 fold higher compared to the control subjects and this increase was not seen in male MDD subjects, suggesting conserved responses to stress in human and mouse. CCR5 is a seven-transmembrane G protein-coupled receptor expressed in microglia, astrocytes and neurons in diverse brain regions. Ligand activation of CCR5 has been show to suppress adenylyl cyclase, activate PI3K/AKT and MAPK signaling and alter intracellular Ca2+ mobilization, all of which can influence synaptic function. Based on these observations, we hypothesize that in female mice, defeat stress induces peripheral increase of CCL5 and its interaction with CCR5 in the brain dysregulates synaptic plasticity and promotes stress-susceptibility. We propose to modulate CCL5 in the periphery or manipulate the CCL5/CCR5 signaling, either pharmacologically or genetically in the PFC, and use a battery of neurobehavioral tests, immunological and molecular techniques to test the role of CCL5 and CCR5 in stress-susceptibility in females, and compare the responses to male mice. We will also investigate whether stress-induced neurovascular damage and associated blood brain barrier leakage may facilitate peripheral CCL5 infiltration to the brain. Lastly we will investigate whether oral application of a FDA approved CCR5 antagonist is effective in treating mice with depression-like phenotype and to compare its efficacy with antidepressant fluoxetine. We believe our approach will greatly enhance our understanding of the pathophysiology underlying depression in female and fill the gap in current scientific knowledge on sex-specific periphery and central mechanisms underlying depressive disorder. The treatment intervention proposed in the application will provide immediate bench-to-bed translation and may significantly improve the health and lives of veterans affected by the stress disorders including depression, anxiety disorders and posttraumatic stress disorders (PTSD), particularly relevant to the health and wellbeing of female veterans.