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.

项目概要/摘要 慢性免疫激活是现代艾滋病毒的主要标志之一，尽管 抗逆转录病毒疗法（ART）抑制病毒复制。这种慢性免疫激活很大程度上是介导的 由骨髓系细胞，包括单核细胞、巨噬细胞和小胶质细胞。这表明了迫切需要 开发新的抗炎策略，在以下情况下有效抑制骨髓激活 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） 是最有前途的新型抗炎药物之一。然而，CBD 对 HIV/SIV 的影响与相关 炎症的情况尚不清楚，因为还没有研究评估其抗炎特性 SIV/猕猴 HIV 模型中的大麻二酚 (CBD)。迫切需要更好地对抗艾滋病毒 ART 时代的相关炎症。鉴于我们在免疫调节方面的知识存在差距 为了研究大麻素的影响，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 器官之间的差异表达。我们的数据表明，刺激这些受体会抑制内源性 和脂多糖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，以及 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 在外周和体内发挥抗炎特性的机制 脑。此外，我们的研究结果将填补有关炎症机制的知识的关键空白 当前 ART 时代潜在的中枢神经系统功能障碍。