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: 10472461
• 负责人: Norbert E Kaminski
• 金额: $ 51.45万
• 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/10472461
• 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; Persons; 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.

项目概要/摘要 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 导致手部疾病的事件是持续的低水平慢性炎症，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 HIV 相关痴呆 (HAD) 患者的水平升高。 HIV感染的一个特点是慢性、系统性 炎症部分是通过肠道微生物衍生产物的易位而引起的，从而激活 单核细胞并促进穿过血脑屏障（BBB）的迁移。进入后，单核细胞被激活 释放神经毒性因子和促炎因子（例如 IL-1），这些因子被认为有助于导致 HAND。 最近，有证据表明炎症小体激活作为一种贡献的重要性 神经炎症和 HAND 的机制。本申请中提供的初步结果表明 IL-1 分泌证明，单核细胞中炎症小体的激活会促进星形胶质细胞炎症。 这些发现支持单核细胞中炎症小体激活作为驱动机制的关键作用 神经炎症。特别是，对死后 HIV 患者的脑组织进行免疫组织细胞化学分析 HAD 显示促炎性 CD16+ 单核细胞显着浸润。相比之下，大麻素暴露 我们和其他人已经报道过，在 HIV 感染患者中显示出抗炎特性。反 大麻的炎症特性很大程度上归因于经典配体，Δ9-四氢大麻酚 （THC），通过大麻素受体（CB）1和非精神药物发挥精神活性 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，代表了了解 CB2 在限制 HIV 相关性中的作用的潜在策略 神经炎症。事实上，初步结果表明 CB2 选择性激动剂会损害单核细胞 IL-1 的分泌是炎症和炎性小体激活的标志。建议进行机理研究 检验假设：来自使用 HIV+ 受试者的非大麻的 CD16+ 单核细胞表现出更大的 与使用 HIV+ 受试者的大麻相比，炎症小体的形成和随后的星形胶质细胞激活， 这与吸食大麻的频率有关。