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

摘要/摘要 重性抑郁症（MDD）是一种广泛的心理障碍，影响约7%的人口， 美国退伍军人中的患病率甚至更高。据估计，约30%的业务 持久自由（OEF）和伊拉克自由行动（OIF）的退伍军人受到抑郁症的影响。性 抑郁症的二型性是有据可查的。女性和男性在患病率、症状 表现和抗抑郁治疗的反应。然而，大多数科学研究 由于实验限制，主要在男性模型中进行。慢性社交失败 压力（CSDS）是研究抑郁症最成熟的模型之一， 男性抑郁症最近，Russo博士的实验室开发了一种女性CSDS范例， 抑郁样的行为，并已在我们的实验室采用。 外周炎症细胞因子的诱导有助于抑郁样行为， 人类和实验模型。以前，人们发现应激诱导的外周血IL-6起着重要的作用。 在确定雄性小鼠的应激敏感性中起重要作用。外周炎症的特征 CSDS后雌性小鼠的应激敏感性与血浆C- C基序趋化因子配体（CCL 5），但不与IL-6。在人类受试者中也报告了更高水平的CCL 5 与男性相比，女性患有MDD和外周CCL 5水平较高，暗示性二态性 CCL 5表达与抑郁症之间的相互作用。基因表达分析显示，CCL 5受体 在易受压力影响的雌性小鼠中，CCR 5在前额叶皮层（PFC）中显著升高， 已知在抑郁症中起重要作用，这种增加在压力敏感的雄性小鼠中没有观察到。 与人类MDD RNA-seq数据的交叉检验显示，在女性MDD受试者中， 腹内侧PFC是对照组的2.8倍， 男性MDD受试者，表明人类和小鼠对应激的保守反应。 CCR 5是一种七跨膜G蛋白偶联受体，在小胶质细胞、星形胶质细胞和胶质细胞中表达。 不同脑区的神经元。CCR 5配体活化已显示抑制腺苷酸环化酶， 激活PI 3 K/AKT和MAPK信号并改变细胞内Ca 2+动员，所有这些都可以影响 突触功能基于这些观察结果，我们假设在雌性小鼠中，失败压力诱导 CCL 5的外周增加及其与脑中CCR 5的相互作用使突触可塑性失调， 促进压力敏感性。我们建议在外周调节CCL 5或操纵CCL 5/CCR 5， 信号，无论是在前额叶皮层的神经或遗传，并使用一组神经行为测试， 免疫学和分子技术来测试CCL 5和CCR 5在女性应激易感性中的作用， 并比较雄性小鼠的反应。我们还将研究应激诱导的神经血管 损伤和相关的血脑屏障渗漏可促进外周CCL 5向脑的浸润。 最后，我们将研究FDA批准的CCR 5拮抗剂的口服应用是否有效治疗 小鼠抑郁样表型，并比较其疗效与抗抑郁药氟西汀。 我们相信，我们的方法将大大提高我们的理解的病理生理基础 填补了目前科学界对女性抑郁症的性别特异性外周和中枢认知的差距， 抑郁症的潜在机制申请中提出的治疗干预将 提供即时的板凳到床的翻译，并可能显着改善退伍军人的健康和生活 受应激障碍影响，包括抑郁症、焦虑症和创伤后应激障碍 创伤后应激障碍（PTSD），特别是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.