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: 10455888
• 负责人: Dionna Whitney Williams
• 金额: $ 16.27万
• 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/10455888
• 关键词: Affect; Animal Model; Anti-Inflammatory Agents; Antiviral Agents; Antiviral Therapy; Biological; Brain; CCL4 gene; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Cell Lineage; Chronic; Data; Development; Disease; Effectiveness; Functional disorder; GPR55 receptor; HIV; HIV Infections; Inflammation; Inflammatory; Knowledge; Macaca; Macaca mulatta; Mediating; Microglia; Modeling; Modernization; Myelogenous; Myeloid Cells; Organ; Peripheral; Pharmaceutical Preparations; Property; Risk Factors; SIV; Source; Tissues; Viral; Viral Genes; Virus Replication; Work; antiretroviral therapy; comorbidity; cytokine; endogenous cannabinoid system; immune activation; immunoregulation; insight; macrophage; monocyte; neuroinflammation; phytocannabinoid; receptor; transcriptome

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 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是通过 由髓系细胞，包括单核细胞、巨噬细胞和小胶质细胞。这表明了一种迫切的需求 开发新的抗炎策略，在以下情况下有效地抑制髓系激活 慢性艾滋病毒感染和治疗。大麻素，特别是植物大麻素(CBD)是 是最有前途的新型抗炎药之一。然而，CBD对HIV/SIV的影响与 炎症尚不清楚，因为还没有研究评估其抗炎特性。 在艾滋病毒SIV/猕猴模型中使用大麻二酚(CBD)。迫切需要更好地对抗艾滋病毒-- 艺术时代的相关炎症。鉴于我们对免疫调节剂的了解存在差距 大麻素的影响，我们建议对病毒抑制的恒河猴进行CBD给药研究 模型(ART-SIV)。常驻组织巨噬细胞表达功能性CB1、CB2和GPR55，尽管有 器官之间的表达是可变的。我们的数据显示，刺激这些受体会抑制内源性 和内毒素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一个来源。 SIV-ART模型。因此，我们建议1)评估CBD对髓系免疫激活的影响，2) 确定CBD对髓系抗病毒信号的影响，以及3)确定CBD对单核细胞的影响 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在外周和脑内发挥抗炎作用的机制 大脑。此外，我们的发现将填补有关炎症机制的知识的一个关键空白。 当前ART时代潜在的中枢神经系统功能障碍。