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

CCL5/CCR5轴在抑郁症中的性别特异性作用及其治疗意义

• 批准号: 10364861
• 负责人: Jun Wang
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364861
• 关键词: Address; Adenylate Cyclase; Adopted; Affect; Antidepressive Agents; Anxiety Disorders; Astrocytes; Beds; Behavior; Blood - brain barrier anatomy; Brain; Brain region; CCR1 gene; CCR5 gene; Cells; Chemotactic Factors; Chronic; Clinical Research; Data; Depressive disorder; Disease; Exhibits; Experimental Models; Extravasation; FDA approved; Female; Fluoxetine; Freedom; Functional disorder; Gene Expression Profiling; General Population; Genetic; Glutamates; Health; Human; Immune; Immunologics; Infiltration; Inflammation; Inflammatory; Interleukin-6; Intervention; Investigation; Knowledge; Laboratories; Lead; Ligands; MAP Kinase Gene; Major Depressive Disorder; Mediating; Mental Depression; Mental Health; Mental disorders; Microglia; Modeling; Molecular; Monoclonal Antibodies; Mus; Natural Killer Cells; Neuraxis; Neurons; Oral; Outcome; PI3K/AKT; Pathogenesis; Pathology; Patients; Peripheral; Personal Satisfaction; Pharmacology; Phenotype; Plasma; Play; Population; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Prevalence; Protocols documentation; RANTES; Receptor Activation; Reporting; Role; Sex Differences; Signal Transduction; Stress; Symptoms; Synapses; Synaptic plasticity; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Translating; Translations; Treatment Efficacy; Up-Regulation; Veterans; Woman; antagonist; base; biological adaptation to stress; blood-brain barrier permeabilization; cell type; chemokine; cytokine; depression model; human female; human subject; improved; male; men; monocyte; mouse model; neurobehavioral test; neurovascular; neurovascular injury; novel; novel therapeutics; operation; receptor; resilience; response; seven-transmembrane G-protein-coupled receptor; sex; sexual dimorphism; social defeat; social stress; stress disorder; synaptic function; transcriptome sequencing

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.

摘要/摘要 重度抑郁症 (MDD) 是一种广泛存在的心​​理障碍，影响约 7% 的美国人 美国退伍军人的患病率甚至更高。据估计，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。性 抑郁症的二态性是有据可查的。女性和男性在患病率、症状方面存在差异 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。长期的社会挫败 压力（CSDS）是研究抑郁症最完善的模型之一，并且在很大程度上仅限于研究 男性抑郁症。最近，Russo 博士的实验室开发了一种女性 CSDS 范例，该范例能够持续产生 雌性小鼠的类似抑郁行为，此后已在我们的实验室中采用。 外周炎症细胞因子的诱导导致抑郁样行为 人类和实验模型中。此前，人们发现应激诱导的外周IL-6发挥着重要作用。 在确定雄性小鼠的应激敏感性中发挥重要作用。周围炎症的特征 CSDS 后的雌性小鼠发现应激敏感性与血浆 C-水平呈正相关 C 基序趋化因子配体 (CCL5)，但不与 IL-6 结合。据报道，人类受试者中 CCL5 水平较高 与男性相比，女性患有 MDD 且外周 CCL5 水平更高，这意味着性别二态性 CCL5 表达与抑郁之间的相互作用。基因表达分析显示 CCL5 受体 在压力敏感的雌性小鼠中，前额皮质（PFC）（大脑区域）的 CCR5 显着较高 已知在抑郁症中发挥重要作用，并且在对压力敏感的雄性小鼠中没有发现这种增加。 与人类 MDD RNA-seq 数据的交叉检查表明，在女性 MDD 受试者中，CCR5 水平 与对照组相比，腹内侧 PFC 增加了 2.8 倍，而这种增加在 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，在小胶质细胞、星形胶质细胞和 不同大脑区域的神经元。 CCR5 的配体激活已被证明可以抑制腺苷酸环化酶， 激活 PI3K/AKT 和 MAPK 信号传导并改变细胞内 Ca2+ 动员，所有这些都会影响 突触功能。基于这些观察，我们假设在雌性小鼠中，失败压力会导致 CCL5 的外周增加及其与大脑中 CCR5 的相互作用会失调突触可塑性和 促进压力敏感性。我们建议在外围调制 CCL5 或操纵 CCL5/CCR5 PFC 中的药理学或遗传信号传导，并使用一系列神经行为测试， 免疫学和分子技术来测试 CCL5 和 CCR5 在女性应激易感性中的作用， 并比较与雄性小鼠的反应。我们还将研究压力是否会诱发神经血管 损伤和相关的血脑屏障渗漏可能会促进外周 CCL5 渗入大脑。 最后，我们将研究口服 FDA 批准的 CCR5 拮抗剂是否能有效治疗 具有抑郁样表型的小鼠，并比较其与抗抑郁药氟西汀的疗效。 我们相信我们的方法将极大地增强我们对潜在病理生理学的理解 女性抑郁症，填补了当前关于特定性别外围和中枢科学知识的空白 抑郁症的潜在机制。申请中提出的治疗干预措施将 提供即时的从替补到床上的翻译，可以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），特别与女性退伍军人的健康和福祉相关。