Cannabinoids Modulate Immune Cell-provoked Astrocyte Functions to Suppress HIV-Associated Neuroinflammatory Responses

大麻素调节免疫细胞引发的星形胶质细胞功能，抑制 HIV 相关的神经炎症反应

基本信息

批准号：
9920700
负责人：
Norbert E Kaminski
金额：
$ 48.72万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920700
关键词：
AIDS dementia Address Agonist Anti-Inflammatory Agents Antigen-Presenting Cells Antiviral Agents Astrocytes Autoantigens Biological Blood - brain barrier anatomy Blood Circulation CD3 Antigens CD8-Positive T-Lymphocytes CD8B1 gene CXCL10 gene Cannabinoids Cannabis Cell Death Cell physiology Cells Chronic Coculture Techniques Data Dendritic Cells Event Exhibits FCGR3B gene Glutamates HIV HIV-associated neurocognitive disorder Health Human Immune Immune response Impaired cognition Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferon Type II Interferon-alpha Interleukin 7 Receptor Interleukin-6 Leukocytes Life Expectancy Link Mediating Neurocognitive Deficit Neurons Patients Peptides Phenotype Plasma Process Production Property Recombinant Interferon Residual state Rest Role Shapes Stimulus Surface System T memory cell T-Cell Activation TLR7 gene Testing Tetrahydrocannabinol Virion antiretroviral therapy cannabinoid treatment chronic infection cognitive function cytokine genetic signature immune activation marijuana user microbial monocyte neuroinflammation neurotoxic novel receptor upregulation recruit response uptake

项目摘要

PROJECT SUMMARY An estimated 37 million people worldwide are infected with human immunodeficiency virus (HIV). Combined antiretroviral therapy (ART) has turned HIV into a chronic infection with significantly longer life expectancy. New health issues have surfaced as HIV patients live longer. Specifically, 50% of HIV-infected (HIV+) individuals exhibit neurocognitive impairment, termed HIV-associated neurocognitive disorders (HAND). A key event leading to HAND is persistent low-level chronic neuroinflammation resulting in neuronal damage and cell death. A major contributor to HIV-induced neuroinflammation is activated monocytes, which are significantly elevated in patients’ with HIV-associated dementia. Activated, CD16+ monocytes are infected by HIV in the periphery and migrate across the blood-brain barrier (BBB) to release HIV virions and neurotoxic and proinflammatory factors. Before entering the CNS, resting (CD16–) monocytes transition into the CD16+ through poorly understood mechanisms including elevated interferon alpha (IFNα), a potent antiviral cytokine produced by plasmacytoid dendritic cells (pDC), an observation consistent with the IFNα gene signature in monocytes from HIV patients. Chronic IFNα production in HIV patients has been linked to neurocognitive impairment. In parallel, IFNα also activates CD8+ T cells, which are recruited from systemic circulation to cross the BBB. Once in the perivascular space, activated monocytes and CD8+ T cells interact with astrocytes to drive a chronic neuroinflammatory response leading to destruction of neurons and declining cognative function. Interestingly, cannabis, which has constituents (e.g., Δ9-tetrahydrocannabinol (THC)) possessing immune suppressive and anti-inflammatory activity, is widely used (approximately 25-37%) by HIV patients. The beneficial vs. deleterious effects of cannabinoid therapy in HIV patients remains unknown and understudied. Preliminary results show that THC suppresses IFNα-mediated CD16– to CD16+ monocyte transition as well as IL-7 receptor upregulation on CD8+ T cells. Moreover, HIV+ marijuana-users (MJ+) have fewer circulating CD16+ monocytes compared to HIV+MJ-. Preliminary data is also presented using a novel all human coculture system demonstrating that both monocytes and CD8+ T cells, when cocultured with astrocytes significant drive the secretion of astrocyte-derived inflammatory mediators, including IL-6 and IP-10, a response suppressed by THC. Mechanistic studies are proposed to test the hypothesis: Cannabinoids suppress interferon-α-mediated monocyte and CD8+ T cell activation in the periphery and their detrimental effects on astrocyte function, all of which are key processes in HIV-associated chronic neuroinflammation.

项目概要据估计，全世界有 3700 万人感染人类免疫缺陷病毒 (HIV)。抗逆转录病毒疗法（ART）已将艾滋病毒转变为慢性感染，预期寿命显着延长。随着艾滋病毒患者的寿命延长，新的健康问题也随之出现，具体来说，50% 的艾滋病毒感染者（HIV+）。个体表现出神经认知障碍，称为艾滋病毒相关神经认知障碍（HAND）。导致 HAND 的事件是持续的低水平慢性神经炎症，导致神经元损伤和细胞 HIV 引起的神经炎症的一个主要因素是激活的单核细胞，其显着增加。 HIV 相关痴呆患者的 CD16+ 单核细胞在感染 HIV 后升高。外周细胞并穿过血脑屏障 (BBB) 释放 HIV 病毒颗粒和神经毒性物质促炎因子在进入 CNS 之前，静息 (CD16-) 单核细胞转变为 CD16+ 通过我们知之甚少的机制，包括干扰素α (IFNα) 升高，这是一种有效的抗病毒细胞因子由浆细胞样树突状细胞 (pDC) 产生，这一观察结果与 IFNα 基因特征一致 HIV 患者的单核细胞的慢性 IFNα 产生与神经认知有关。与此同时，IFNα 还会激活 CD8+ T 细胞，这些细胞从体循环中招募来交叉。一旦进入血管周围空间，激活的单核细胞和 CD8+ T 细胞就会与星形胶质细胞相互作用，引起慢性神经炎症反应，导致神经元破坏和认知功能下降。大麻，其成分（例如，Δ9-四氢大麻酚（THC））具有免疫功能抑制和抗炎活性，被 HIV 患者广泛使用（约 25-37%）。大麻素治疗对艾滋病毒患者的有益与有害影响仍然未知，也没有得到充分研究。初步结果表明，THC 抑制 IFNα 介导的 CD16- 到 CD16+ 单核细胞的转变以及 CD8+ T 细胞上的 IL-7 受体上调此外，HIV+ 大麻使用者 (MJ+) 的循环量较少。还使用新型全人类共培养物提供了 CD16+ 单核细胞与 HIV+MJ- 的初步数据。系统证明，当与星形胶质细胞共培养时，单核细胞和 CD8+ T 细胞均显着驱动星形胶质细胞衍生的炎症介质的分泌，包括 IL-6 和 IP-10，这是一种被抑制的反应 THC 的机制研究旨在检验这一假设：大麻素抑制干扰素 α 介导的。外周单核细胞和 CD8+ T 细胞的激活及其疼痛对星形胶质细胞功能的影响，所有这些这是艾滋病毒相关慢性神经炎症的关键过程。