Cannabis use frequency and its impact on monocyte-mediated inflammation in HIV patients

大麻使用频率及其对艾滋病毒患者单核细胞介导的炎症的影响

• 批准号: 10153106
• 负责人: Norbert E Kaminski
• 金额: $ 51.2万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10153106
• 关键词: AIDS dementia; Agonist; Anti-Inflammatory Agents; Astrocytes; Automobile Driving; Autopsy; Blood - brain barrier anatomy; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Cannabis; Cell Death; Cells; Chronic; Coculture Techniques; Event; Exhibits; FCGR3B gene; Frequencies; Glutamates; HIV; HIV Infections; HIV-associated neurocognitive disorder; Health; Human; Immunohistocytochemistry; Impairment; Individual; Infiltration; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 alpha; Interleukin-1 beta; Interleukin-18; Life Expectancy; Ligands; Mediating; Neurocognitive Deficit; Neurons; Pathway interactions; Patients; Property; Proteins; Regulation; Reporting; Role; Surface; Testing; Tetrahydrocannabinol; antiretroviral therapy; brain tissue; cannabinoid receptor; cell type; chronic infection; in vivo; marijuana use; microbial; migration; monocyte; neuroinflammation; neurotoxic; response; systemic inflammatory response; transcriptomics

PROJECT SUMMARY/ABSTRACT 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 disorder (HAND). A key event leading to HAND is persistent low-level chronic inflammation 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 (HAD). A hallmark of HIV infection is chronic, systemic inflammation in part through translocation of microbial derived products from the gut which, activates monocytes and promote migration across the blood-brain barrier (BBB). Upon entry, activated monocytes release neurotoxic and proinflammatory factors (e.g., IL-1), which are thought to contribute to HAND. Recently, evidence has emerged implicating the importance of inflammasome activation as a contributing mechanism to neuroinflammation and HAND. Preliminary results presented in this application show that inflammasome activation in monocytes, as evidenced by IL-1 secretion, promotes astroglial cell inflammation. These findings support a critical role for inflammasome activation in monocytes as a mechanism driving neuroinflammation. In particular, immunohistocytochemistry of brain tissue from post-mortem HIV patients with HAD showed significant infiltration of proinflammatory CD16+ monocytes. By contrast, cannabinoid exposure displays anti-inflammatory properties in HIV-infected patients, which we and others have reported. The anti- inflammatory properties of cannabis are attributed largely to the canonical ligand, ∆9-tetrahydrocannabinol (THC), which exerts psychotropic activity through cannabinoid receptor (CB) 1 and the non-psychotropic- mediating CB2, while cannabidiol (CBD) does not act through CB1/CB2. Likewise, the CB2 selective agonist, JWH-015, represents a potential strategy for understanding the role of CB2 in limiting HIV-associated neuroinflammation. In fact, preliminary results demonstrate that a CB2 selective agonist impairs monocyte secretion of IL-1, a hallmark of inflammation and inflammasome activation. Mechanistic studies are proposed to test the hypothesis: CD16+ monocytes from non-cannabis using HIV+ subjects exhibit greater inflammasome formation and subsequent astrocyte activation compared to cannabis using HIV+ subjects, which is associated with the frequency of cannabis use.

项目摘要/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（HAND）。钥匙 导致手的事件是持续的低级慢性感染，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相关痴呆症患者的患者（HAT）升高。艾滋病毒感染的标志是慢性，全身性的 炎症部分是通过从肠道中易位的微生物衍生产物的易位 单核细胞并促进跨血脑屏障（BBB）迁移。进入后，激活的单核细胞 释放神经毒性和促炎性因子（例如IL-1），被认为有助于手。 最近，有证据表明炎性体激活的重要性是有助于 神经炎症和手的机制。本申请中提出的初步结果表明 IL-1分泌证明，单核细胞中的炎症体激活促进了星形胶质细胞注射。 这些发现支持单核细胞中炎性体激活的关键作用，作为一种机制驱动 神经炎症。特别是，来自死后HIV患者的脑组织的免疫组织细胞化学 已经显示出促炎性CD16+单核细胞的显着浸润。相比之下，大麻素暴露 在我们和其他人报告的HIV感染患者中显示抗炎特性。反 - 大麻的炎症特性主要归因于规范配体∆9-四氢大麻醇 （THC），通过大麻素受体（CB）1和非精神上的 - 介导CB2，而大麻二酚（CBD）不通过CB1/CB2起作用。同样，CB2选择性激动剂， JWH-015代表了理解CB2在限制HIV相关的作用的潜在策略 神经炎症。实际上，初步结果表明CB2选择性激动剂会损害单核细胞 IL-1的分泌，这是炎症和炎症体激活的标志。提出了机械研究 测试假设：使用HIV+受试者暴露于非大胆的CD16+单核细胞 与使用HIV+受试者相比 这与大麻使用频率有关。