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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.

项目总结/文摘