Dynamic Cellular Interactions Associated with Inflammatory Monocyte Accumulation in the Neurovasculature with Social Stress

与社交压力下神经血管系统中炎症性单核细胞积聚相关的动态细胞相互作用

• 批准号: 10348144
• 负责人: Jonathan P Godbout
• 金额: $ 51.56万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348144
• 关键词: Address; Anxiety; Behavioral; Blood Circulation; Bone Marrow; Brain; Brain region; CCL2 gene; CSF1R gene; Cells; Chemosensitization; Data; Development; Dextrans; Endothelial Cells; Endothelium; Event; Female; Fingerprint; Gene Expression Profiling; Genetic Transcription; Goals; Health; Human; Immunologics; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Intervention; Knowledge; Ligands; Mediating; Mental Depression; Mental Health; Messenger RNA; Microglia; Mus; Neurons; PTGS2 gene; Prevalence; Principal Investigator; Production; Prostaglandins; Psychological Stress; Psychosocial Stress; Purinoceptor; Quality of life; Recruitment Activity; Reporter; Reporting; Role; Signal Transduction; Specificity; Stress; Testing; Therapeutic Intervention; Work; antagonist; anxiety-like behavior; base; chemokine; cyclooxygenase 2; cytokine; mRNA Expression; male; monocyte; mouse model; neuroinflammation; neuropsychiatry; neurovascular; new therapeutic target; novel; pre-clinical; prevent; programs; recruit; response; social defeat; social stress

Program Director/Principal Investigator (Sheridan, JF & Godbout JP): PROJECT SUMMARY/ABSTRACT: Dynamic inflammatory signaling in the brain may have a causative role in anxiety. We report that repeated social defeat (RSD) in mice induces sympathetic-mediated release of primed monocytes from the bone marrow that are actively recruited to the brain. Collectively, we show that RSD promotes prolonged anxiety-like behavior that depends on activation of microglia and recruitment of inflammatory monocytes to threat appraisal regions of the brain. This application demonstrates that microglial recruitment of IL-1β producing monocytes to neurovascular endothelium is necessary for the potentiation of anxiety-like behavior in response to social stress. Despite this knowledge, three key mechanistic questions remain to be answered, which will allow for the development of novel interventions for treatment of neuropsychiatric complications associated with stress: 1) How does RSD activate microglia in threat appraisal regions? 2) How are inflammatory monocytes selectivity recruited to neurovascular endothelium in threat appraisal regions? 3) What are the key factors produced by neurovascular endothelia cells that potentiate neuroinflammation and anxiety? We show that microglial activation in response to RSD depends on neuronal activation within threat appraisal regions. Moreover, preliminary evidence suggests that this is mediated by activation of the purinergic receptor, P2RX7, on microglia. Novel data presented here show that monocyte recruitment and the development of anxiety-like behavior after RSD requires microglial activation. Furthermore, cell-specific transcriptional profiling indicates that microglia recruit monocytes to the brain via chemokine ligand (CCL2) secretion. These recruited monocytes produce IL-1and promote anxiety-like behavior by endothelial IL-1 Receptor-1 activation. Notably, this IL-1R1 activation is associated with increased neurovascular expression of COX2, the enzyme that synthesizes neuroactive prostaglandins. Thus, the goal of this project is to test the hypothesis that recruitment and subsequent interaction of inflammatory monocytes with neurovascular endothelial cells is critical for the augmentation of neuroinflammation and potentiation of anxiety-like behavior following RSD. To address this hypothesis, three specific aims are proposed. In Aim-1, we will ascertain the extent to which RSD-induced microglial activation is dependent on stimulation of the P2RX7 purinergic receptor. In Aim-2, we will determine the degree to which microglial production of CCL2 is required for monocyte recruitment to threat appraisal regions and the induction of anxiety-like behavior after RSD. In Aim-3, we will assess the role of endothelial COX2 following RSD and determine other key factors produced by IL-1R1-stimulated endothelial cells that facilitate anxiety-like behavior after RSD. Understanding how microglial recruitment of IL-1β producing monocytes to threat appraisal regions potentiates neuroinflammation and anxiety-like behavior will lead to new interventions for neuropsychiatric complications associated with stress. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

项目总监/首席研究员（Sheridan、JF 和 Godbout JP）： 项目概要/摘要： 大脑中的动态炎症信号可能与焦虑有关。我们报告重复 小鼠的社交失败（RSD）诱导交感神经介导的单核细胞从骨髓中释放 被积极地招募到大脑中。总的来说，我们表明 RSD 会促进长期的焦虑样症状 依赖于小胶质细胞激活和炎症单核细胞募集来进行威胁评估的行为 大脑区域。该应用表明，小胶质细胞招募产生 IL-1β 的单核细胞 神经血管内皮对于增强响应社交的焦虑样行为是必需的 压力。尽管有了这些知识，三个关键的机制问题仍有待回答，这将允许 开发治疗与压力相关的神经精神并发症的新干预措施： 1）RSD如何激活威胁评估区域的小胶质细胞？ 2) 炎症单核细胞如何 威胁评估区域神经血管内皮细胞的选择性招募？ 3）关键因素是什么 由神经血管内皮细胞产生，会加剧神经炎症和焦虑？我们表明 响应 RSD 的小胶质细胞激活取决于威胁评估区域内的神经元激活。 此外，初步证据表明这是由嘌呤能受体 P2RX7 的激活介导的， 关于小胶质细胞。这里提供的新数据表明单核细胞的募集和焦虑样的发展 RSD 后的行为需要小胶质细胞激活。此外，细胞特异性转录谱表明 小胶质细胞通过趋化因子配体 (CCL2) 分泌将单核细胞招募到大脑。这些招募的 单核细胞产生 IL-1并通过内皮 IL-1 受体 1 激活促进焦虑样行为。尤其， IL-1R1 的激活与 COX2 的神经血管表达增加有关，COX2 是一种酶， 合成神经活性前列腺素。因此，该项目的目标是检验以下假设：招聘 随后炎症单核细胞与神经血管内皮细胞的相互作用对于 RSD 后神经炎症加剧和焦虑样行为增强。为了解决这个问题 假设，提出了三个具体目标。在 Aim-1 中，我们将确定 RSD 引起的程度 小胶质细胞的激活依赖于 P2RX7 嘌呤能受体的刺激。在 Aim-2 中，我们将确定 单核细胞募集以进行威胁评估所需的小胶质细胞产生 CCL2 的程度 RSD 后区域和焦虑样行为的诱导。在 Aim-3 中，我们将评估内皮细胞的作用 COX2 遵循 RSD 并确定由 IL-1R1 刺激的内皮细胞产生的其他关键因子 RSD 后促进类似焦虑的行为。了解小胶质细胞如何募集 IL-1β 产生 单核细胞进入威胁评估区域会增强神经炎症，焦虑样行为将导致新的 针对与压力相关的神经精神并发症的干预措施。 PHS 398/2590（修订版 06/09） 页面延续 格式页面