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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要慢性免疫激活是现代艾滋病毒的主要标志之一，尽管有效抑制病毒复制的抗逆转录病毒疗法（ART）。这种慢性免疫激活在很大程度上介导由髓样细胞细胞，包括单核细胞，巨噬细胞和小胶质细胞。这表明了急需制定新的抗炎策略，这些策略可有效抑制在慢性HIV感染和治疗。大麻素，特别是植物大麻素大麻二酚（CBD）是最有希望的新抗炎药之一。但是，CBD对HIV/SIV相关的影响炎症尚不清楚，因为没有研究评估 HIV的SIV/猕猴模型中的大麻二醇（CBD）。迫切需要更好地抵消HIV- 在艺术时代相关的炎症。考虑到我们有关免疫调节的差距大麻素的影响，我们提出了有关病毒抑制猕猴中CBD给药的研究型号（艺术活动）。居民组织巨噬细胞表达功能性CB1，CB2和GPR55，尽管有器官之间的可变表达。我们的数据表明，刺激这些受体抑制内源性以及LPS诱导的促炎和抗病毒基因，同时增加了有效的抗炎细胞因子。我们确定这些细胞因子是我们的周围和中枢神经系统中慢性炎症的根源 SIV-ART模型。因此，我们建议1）评估CBD对髓样免疫激活的影响，2）确定CBD对髓样抗病毒特征的影响，3）定义CBD对单核细胞的影响以及小胶质细胞神经炎症和神经保护转录组。我们预计我们的工作将提供深入了解CBD在外围和在脑。此外，我们的发现将填补有关炎症机制知识的关键空白在当前艺术时代的CNS功能障碍。