Cannabidiol and Macrophage Chronic Inflammation in a Virally Suppressed Rhesus Macaque Model

病毒抑制的恒河猴模型中的大麻二酚和巨噬细胞慢性炎症

• 批准号: 10754708
• 负责人: Dionna Whitney Williams
• 金额: $ 11.27万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754708
• 关键词: Affect; Agonist; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Antiviral Response; Antiviral Therapy; Anxiety; Biological; Blood; Brain; CCL2 gene; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Cannabis; Cell Lineage; Cells; Central Nervous System; Chronic; Data; Development; Disease; Effectiveness; Exposure to; Functional disorder; GPR55 receptor; Genes; Goals; HIV; HIV Infections; Impaired cognition; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Activation; Interferon-beta; Interferons; Interleukin-10; Interleukin-12; Interleukin-6; Knowledge; Macaca; Macaca mulatta; Macrophage; Mediating; Mediator; Medical; Mental Depression; Microglia; Modeling; Modernization; Myelogenous; Myeloid Cells; NF-kappa B; Nausea; Nervous System Physiology; Neurodegenerative Disorders; Oral Administration; Organ; Pain; Pathway interactions; Peripheral; Peripheral Nervous System; Persons; Pharmaceutical Preparations; Population; Prevalence; Process; Property; Receptor Inhibition; Recreation; Regulator Genes; Risk Factors; Role; SIV; Signal Transduction; Source; TNF gene; TNFSF10 gene; Therapeutic; Tissues; Viral; Viral Genes; Virus Replication; Work; antiretroviral therapy; anxiety symptoms; comorbidity; cytokine; daily functioning; depressive symptoms; endogenous cannabinoid system; genetic signature; immune activation; immunoregulation; insight; interest; monocyte; neuroAIDS; neuroinflammation; neuroprotection; novel; phytocannabinoid; receptor; reduce symptoms; transcriptome; transcriptome sequencing; transcriptomics; wasting

PROJECT SUMMARY/ABSTRACT Chronic, immune activation is one of the major hallmarks of HIV in the modern era, despite the effectiveness of antiretroviral therapy (ART) in suppressing viral replication. This chronic immune activation is largely mediated by myeloid-lineage cells, including monocytes, macrophages, and microglia. This demonstrates a critical need to develop new anti-inflammatory strategies that are effective in inhibiting myeloid activation in the context of chronic HIV infection and treatment. Cannabinoids, particularly the phytocannabinoid cannabidiol (CBD) is among the most promising new anti-inflammatory drug. However, the impact of CBD on HIV/SIV associated inflammation is not clear because there have been no studies assessing the anti-inflammatory properties of cannabidiol (CBD) in the SIV/macaque model of HIV. There is a pressing need to better counteract HIV- associated inflammation in the ART era. Given the gap in our knowledge regarding the immunomodulatory effects of cannabinoids, we propose studies on CBD administration in a virally suppressed rhesus macaque model (ART-SIV). Resident tissue macrophages express functional CB1, CB2, and GPR55, though there is variable expression among the organs. Our data show that stimulating these receptors inhibits endogenous and LPS-induced pro-inflammatory and anti-viral genes, while increasing potent anti-inflammatory cytokines. We determined that these cytokines were a source of chronic inflammation in the periphery and CNS in our SIV-ART model. Thus, we propose to 1) evaluate the impact of CBD on myeloid immune activation, 2) determine the effect of CBD on myeloid antiviral signatures, and 3) define the impact of CBD on the monocytic and microglial neuroinflammatory and neuroprotective transcriptome. We anticipate our work will provide insight into the mechanisms by which CBD exerts anti-inflammatory properties, both peripherally and in the brain. Additionally, our findings will fill a critical gap in knowledge regarding the inflammatory mechanisms underlying CNS dysfunction in the current ART era.

项目总结/摘要 慢性免疫激活是现代艾滋病毒的主要标志之一，尽管 抗逆转录病毒疗法（ART）抑制病毒复制。这种慢性免疫激活在很大程度上是由 骨髓系细胞，包括单核细胞、巨噬细胞和小胶质细胞。这表明迫切需要 开发新的抗炎策略，有效抑制骨髓活化， 慢性艾滋病毒感染和治疗。大麻素，特别是植物大麻素大麻二酚（CBD）， 最有前途的新型抗炎药之一。然而，CBD对HIV/SIV相关的影响 炎症是不清楚的，因为还没有研究评估抗炎特性的 大麻二酚（CBD）在HIV的SIV/猕猴模型中的作用。迫切需要更好地对抗艾滋病毒- 在ART时代的相关炎症。鉴于我们对免疫调节的认识存在差距， 大麻素的影响，我们提出研究CBD管理在病毒抑制恒河猴 模型（ART-SIV）。驻留的组织巨噬细胞表达功能性CB 1、CB 2和GPR 55，尽管在细胞中存在着功能性的CB 1、CB 2和GPR 55。 各器官间的差异表达。我们的数据表明，刺激这些受体抑制内源性 和LPS诱导的促炎和抗病毒基因，同时增加有效的抗炎细胞因子。 我们确定这些细胞因子是外周和中枢神经系统慢性炎症的来源， SIV-ART模型因此，我们建议1）评估CBD对骨髓免疫激活的影响，2） 确定CBD对骨髓抗病毒特征的影响，和3）确定CBD对单核细胞的影响。 以及小胶质细胞神经炎性和神经保护性转录组。我们预计我们的工作将提供 深入了解CBD发挥抗炎特性的机制，无论是外周还是 个脑袋此外，我们的发现将填补有关炎症机制知识的关键空白， 当前ART时代潜在的CNS功能障碍。