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: 10619501
• 负责人: Norbert E Kaminski
• 金额: $ 48.89万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619501
• 关键词: AIDS dementia; Agonist; Anti-Inflammatory Agents; Antigen-Presenting Cells; Astrocytes; Autoantigens; Blood - brain barrier anatomy; Blood Vessels; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL10 gene; CXCR3 gene; Cannabinoids; Cannabis; Cell Communication; Cell Death; Cell physiology; Cells; Chronic; Circulation; Coculture Techniques; Data; Deceleration; 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; Persons; Phenotype; Plasma; Process; Production; Property; Receptor Up-Regulation; Recombinant Interferon Alfa; Residual state; Rest; Role; Shapes; Stimulus; Surface; System; T memory cell; T-Cell Activation; TLR7 gene; Testing; Tetrahydrocannabinol; Viral; Virion; antiretroviral therapy; blood-brain barrier crossing; cannabinoid treatment; chronic infection; cognitive function; cytokine; genetic signature; immune activation; immunoregulation; marijuana user; microbial; migration; 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.

项目摘要 全世界估计有3700万人感染了人类免疫缺陷病毒（HIV）。合并 抗逆转录病毒疗法（ART）已将HIV变成一种慢性预期寿命的慢性感染。 随着艾滋病毒患者的寿命更长，新的健康问题浮出水面。具体而言，50％的HIV感染（HIV+） 个体暴露于神经认知障碍，称为HIV相关的神经认知障碍（手）。钥匙 导致手的事件是持续的低级慢性神经炎症，导致神经元损害和细胞 死亡。引起HIV诱导的神经炎症的主要因素是激活的单核细胞，这是显着的 患有HIV相关痴呆的患者的患者升高。激活的，CD16+单核细胞在HIV中感染 周围和跨血脑屏障（BBB）迁移以释放HIV病毒和神经毒性和 促炎性因素。进入CNS之前，静止（CD16-）单核细胞过渡到CD16+ 通过较低的理解机制，包括升高干扰素α（IFNα），潜在的抗病毒细胞因子 由浆细胞类动物树突状细胞（PDC）产生，这是一种与IFNα基因特征一致的观察结果 来自HIV患者的单核细胞。 HIV患者的慢性IFNα产生与神经认知有关 损害。同时，IFNα还激活CD8+ T细胞，这些CD8+ T细胞是从系统循环中募集的 BBB。一旦进入血管周空间，活化的单核细胞和CD8+ T细胞与星形胶质细胞相互作用 驱动慢性神经炎症反应，导致神经元破坏和认知功能下降。 有趣的是，具有免疫的大麻（例如Δ9-四氢大麻酚（THC）） HIV患者广泛使用抑制性和抗炎活性（约25-37％）。这 大麻素治疗对艾滋病毒患者的有益与有害作用尚不清楚和理解。 初步结果表明，THC抑制IFNα介导的CD16-至CD16+单核细胞过渡以及 CD8+ T细胞上的IL-7受体上调。此外，艾滋病毒+大麻 - 用户（MJ+）的循环较少 与HIV+ MJ-相比，CD16+单核细胞。还使用新颖的所有人类共培养提出了初步数据 系统证明单核细胞和CD8+ T细胞都与星形胶质细胞共培养时 星形胶质细胞衍生的炎症介质的分泌，包括IL-6和IP-10，这一反应被抑制了 THC。提出了机械研究以检验假设：大麻素抑制了干涉-α介导的 周围的单核细胞和CD8+ T细胞激活及其对星形胶质细胞功能的有害影响，所有 这是与HIV相关的慢性神经炎症的关键过程。

项目成果

Immunomodulation by cannabinoids: Current uses, mechanisms, and identification of data gaps to be addressed for additional therapeutic application.

• DOI: 10.1016/bs.apha.2021.01.001
• 发表时间: 2021
• 期刊: Advances in pharmacology
• 作者: N. Kaminski;B. Kaplan

The current understanding of the benefits, safety, and regulation of cannabidiol in consumer products.

• DOI: 10.1016/j.fct.2021.112600
• 发表时间: 2021-11
• 期刊: FOOD AND CHEMICAL TOXICOLOGY
• 影响因子: 4.3
• 作者: Li, Jinpeng;Carvajal, Ricardo;Bruner, Leon;Kaminski, Norbert E.
• 通讯作者: Kaminski, Norbert E.

Cannabidiol selectively modulates interleukin (IL)-1β and IL-6 production in toll-like receptor activated human peripheral blood monocytes.

• DOI: 10.1016/j.tox.2021.153016
• 发表时间: 2021-12
• 期刊: TOXICOLOGY
• 影响因子: 4.5
• 作者: Sermet, Sera;Li, Jinpeng;Bach, Anthony;Crawford, Robert B.;Kaminski, Norbert E.
• 通讯作者: Kaminski, Norbert E.