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.

项目总结/摘要 据估计，全世界有3 700万人感染了人体免疫缺陷病毒（艾滋病毒）。组合 抗逆转录病毒疗法（ART）已将艾滋病毒变成一种慢性感染，预期寿命大大延长。 随着艾滋病毒感染者寿命的延长，新的健康问题也浮出水面。50%的艾滋病毒感染者（HIV+） 个体表现出神经认知损害，称为HIV相关的神经认知障碍（HAND）。一个关键 导致HAND的事件是持续性低水平慢性炎症，导致神经元损伤和细胞凋亡。 死亡HIV诱导的神经炎症的一个主要贡献者是活化的单核细胞，其显著地 HIV相关性痴呆（HAD）患者中，艾滋病毒感染的一个标志是慢性、系统性 炎症部分通过肠道微生物衍生产物的移位， 单核细胞并促进穿过血脑屏障（BBB）的迁移。一旦进入，激活的单核细胞 释放神经毒性和促炎因子（例如，IL-1 β），其被认为有助于HAND。 最近，有证据表明炎性小体激活作为一种促进 神经炎症和手的机制。本申请中提出的初步结果表明， 如IL-1 β分泌所证实的，单核细胞中的炎性小体活化促进星形胶质细胞炎症。 这些发现支持单核细胞中炎性小体激活作为驱动炎症反应的机制的关键作用。 神经炎症特别是，从尸检的HIV患者脑组织的免疫组织化学， HAD显示显著的促炎性CD 16+单核细胞浸润。相比之下， 在HIV感染患者中显示抗炎特性，我们和其他人已经报道过。反- 大麻的炎症特性主要归因于典型的配体，β 9-四氢大麻酚 (THC)，它通过大麻素受体（CB）1和非精神活性- 大麻二酚（CBD）不通过CB 1/CB 2起作用。同样，CB 2选择性激动剂， JWH-015，代表了一种了解CB 2在限制HIV相关性疾病中的作用的潜在策略。 神经炎症事实上，初步结果表明，CB 2选择性激动剂损害单核细胞 IL-1 β的分泌是炎症和炎性小体活化的标志。提出了机理研究 为了检验这一假设：来自使用HIV+的非大麻受试者的CD 16+单核细胞表现出更大的 与使用大麻的HIV+受试者相比， 这与大麻的使用频率有关。