Cannabinoid Modulation of Neuroinflammation in Human iPSC Models of HIV Infection

大麻素对 HIV 感染的人类 iPSC 模型中神经炎症的调节

• 批准号: 10647715
• 负责人: ALEXANDER STARR
• 金额: $ 3.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-12-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10647715
• 关键词: Agonist; Anti-Inflammatory Agents; Automobile Driving; Behavior Disorders; Biological Assay; Brain; CASP1 gene; CNR2 gene; Cannabinoids; Cannabis; Cell model; Cells; Central Nervous System; DNA biosynthesis; Disease; Drug Prescriptions; Effectiveness; Enzymes; Event; Experimental Autoimmune Encephalomyelitis; Exposure to; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic Transcription; Glutamates; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; IL18 gene; Immune; Impaired cognition; In Vitro; Individual; Infection; Infiltration; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Kinetics; Knowledge; Label; Learning; Lentivirus; Macrophage; Measures; Mediating; Mediator; Memory; Microglia; Modeling; Molecular; Moods; Morphology; Neurocognitive Deficit; Neuroglia; Neurologic; Neurons; Nuclear; Pathologic; Pathway interactions; Patients; Peripheral; Persons; Plasma; Population; Productivity; Recreational Drugs; Regulation; Risk; Severities; Supplementation; Therapeutic; Therapeutic Intervention; United States; Viral Load result; Virus; Work; antiretroviral therapy; chemokine; cytokine; endogenous cannabinoid system; excitotoxicity; experience; exposed human population; fetal; glial activation; human model; immune system function; immunoregulation; induced pluripotent stem cell; inhibitor; marijuana use; monocyte; motor disorder; neuroAIDS; neuroinflammation; neuroprotection; neurotoxic; neurotoxicity; pharmacologic; prevent; receptor; small molecule; stem cell differentiation; stem cell model; therapeutic target; tool; transmission process; viral DNA

PROJECT SUMMARY / ABSTRACT Despite effective combined antiretroviral therapies, 30-50% of people living with human immunodeficiency virus-1 (HIV) infection experience mood, memory, learning, and/or motor disfunction, collectively labeled HIV associated neurocognitive disorders. Mounting evidence suggests that HIV infects brain-resident macrophages and microglia, providing a persistent reservoir for HIV replication in the central nervous system. Because HIV does not infect neurons, the neurotoxic mechanisms driving neurocognitive decline are likely mediated by infected glia, which become activated and secrete proinflammatory cytokines and chemokines, neurotoxic HIV components, and excitotoxic levels of glutamate. Activation of the NLRP3 inflammasome, an NF-κB-driven assembly that facilitates IL-1β and IL-18 release and initiates pyroptosis, has been identified as an HIV-induced mediator of neurotoxicity. Recent studies suggest that NLRP3 activation is suppressed by activation of cannabinoid receptor 2 (CB2), an immunomodulatory GPCR which has been separately identified as a neuroprotective target in in vitro HIV models. I hypothesize that CB2 agonism decreases HIV-associated macrophage/microglial activation and macrophage/microglia-mediated neurotoxicity by suppressing the NLRP3 inflammasome. This proposal leverages primary human monocyte-derived macrophages (MDMs) in parallel with human induced pluripotent stem cells (iPSC) differentiated into microglia (iMg) and glutamatergic cortical neurons to understand the cell-specific effects of CB2 agonists on HIV infection and subsequent neuroinflammation. This will be accomplished in three aims: (I) identify how CB2 agonism effects macrophage and microglial infection dynamics, broad pro-inflammatory activation, and endocannabinoid system component expression in human models exposed to intact HIV, (II) specifically determine the effects of CB2 agonism on NLRP3 inflammasome priming, assembly, and pro-inflammatory cytokine release, and (III) examine whether CB2 agonism is protective against indirect macrophage- and microglia-mediated neurotoxicity, and whether that protection occurs via modulation of the NLRP3 inflammasome. These studies will increase our understanding of the effects of cannabinoid exposure in HIV- induced neuroinflammation and determine whether CB2 is a potential therapeutic target for NLRP3 inflammasome suppression in HIV infection and other pathologic neuroinflammatory contexts.

项目摘要/摘要 尽管有效的联合抗逆转录病毒疗法，30%-50%的人类感染者 免疫缺陷病毒-1(HIV)感染会出现情绪、记忆、学习和/或运动功能障碍， 共同标记为艾滋病毒相关的神经认知障碍。越来越多的证据表明艾滋病毒会感染 驻留在脑内的巨噬细胞和小胶质细胞，为艾滋病毒在中央的复制提供了持久的储存库 神经系统。因为艾滋病毒不会感染神经元，所以驱动神经认知的神经毒性机制 下降可能是由感染的胶质细胞介导的，胶质细胞被激活并分泌促炎细胞因子 以及趋化因子、神经毒性艾滋病毒成分和谷氨酸的兴奋毒性水平。NLRP3的激活 炎症体是一种由核因子-κB驱动的组件，促进IL-1β和IL-18的释放并引发下垂。 已被确定为艾滋病毒诱导的神经毒性的介体。最近的研究表明，NLRP3的激活是 被大麻素受体2(CB2)激活抑制，一种免疫调节性GPCR已经被 在体外HIV模型中被单独确定为神经保护靶点。我假设CB2激动症 减少HIV相关巨噬细胞/小胶质细胞激活和巨噬细胞/小胶质细胞介导的神经毒性 通过抑制NLRP3炎症体。这项提议利用原代人类单核细胞来源 巨噬细胞(MDM)与人诱导多能干细胞(IPSC)平行分化为小胶质细胞 了解CB2激动剂对HIV感染的细胞特异性影响 以及随之而来的神经炎症。这将通过三个目标来实现：(I)确定CB2激动剂如何 影响巨噬细胞和小胶质细胞感染动力学，广泛的促炎活性，以及 暴露于完整HIV的人体模型中内源性大麻素系统成分的表达，(Ii)特异性 确定CB2激动剂对NLRP3炎症小体启动、组装和促炎的影响 细胞因子的释放，以及(Iii)检查CB2激动剂是否对间接巨噬细胞具有保护作用 小胶质细胞介导的神经毒性，以及这种保护是否通过调节NLRP3而发生 炎症者。这些研究将增加我们对暴露于大麻类药物对艾滋病毒的影响的了解- 诱导神经炎症并确定CB2是否为NLRP3的潜在治疗靶点 HIV感染和其他病理性神经炎性环境中的炎性小体抑制。