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

基本信息

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
项目类别：
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

项目摘要

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，全世界有 3700 万人感染人类免疫缺陷病毒 (HIV)。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。随着艾滋病毒患者的寿命延长，新的健康问题也随之出现，具体来说，50% 的艾滋病毒感染者（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）。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 HIV 引起的神经炎症的一个主要因素是激活的单核细胞，其显着增加。 HIV 相关痴呆 (HAD) 患者的血压升高 HIV 感染的一个特点是慢性、全身性。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，激活单核细胞。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，出现的证据表明炎症小体激活作为一种贡献因素的重要性。本申请中提出的初步结果表明，神经炎症和 HAND 的机制。 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特别是死后 HIV 患者脑组织的免疫组织细胞化学。 HAD 显示促炎 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。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 发挥作用，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 的分泌是炎症和炎症小体激活的标志，建议进行机制研究。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，这与大麻的使用频率有关。