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

• 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
• 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

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，全球有 3700 万人感染人类免疫缺陷病毒 (HIV)。组合 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。 随着艾滋病毒患者寿命的延长，新的健康问题也出现了。具体来说，50% 的 HIV 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）。一把钥匙 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 死亡。 HIV 引起的神经炎症的一个主要贡献者是激活的单核细胞，其显着 患有艾滋病毒相关痴呆症的患者中升高。激活的 CD16+ 单核细胞在体内被 HIV 感染 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 来自艾滋病毒患者的单核细胞。 HIV 患者的慢性 IFNα 产生与神经认知能力有关 损害。同时，IFNα 还激活 CD8+ T 细胞，这些细胞从体循环中招募来交叉 BBB。一旦进入血管周围空间，活化的单核细胞和 CD8+ T 细胞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。 有趣的是，大麻含有具有免疫功能的成分（例如，Δ9-四氢大麻酚（THC）） 抑制和抗炎活性，被 HIV 患者广泛使用（约 25-37%）。这 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+）的流通量较少 CD16+ 单核细胞与 HIV+MJ- 相比。还使用一种新颖的全人类共培养提供了初步数据 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 四氢大麻酚。提出机制研究来检验这一假设：大麻素抑制干扰素 α 介导的 外周单核细胞和 CD8+ T 细胞的激活及其对星形胶质细胞功能的有害影响，所有这些 这是艾滋病毒相关慢性神经炎症的关键过程。