Cannabinoids Modulate Immune Cell-provoked Astrocyte Functions to Suppress HIV-Associated Neuroinflammatory Responses

大麻素调节免疫细胞引发的星形胶质细胞功能，抑制 HIV 相关的神经炎症反应

• 批准号: 10619501
• 负责人: Norbert E Kaminski
• 金额: $ 48.89万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619501
• 关键词: AIDS dementia; Agonist; Anti-Inflammatory Agents; Antigen-Presenting Cells; Astrocytes; Autoantigens; Blood - brain barrier anatomy; Blood Vessels; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL10 gene; CXCR3 gene; Cannabinoids; Cannabis; Cell Communication; Cell Death; Cell physiology; Cells; Chronic; Circulation; Coculture Techniques; Data; Deceleration; Dendritic Cells; Event; Exhibits; FCGR3B gene; Glutamates; HIV; HIV-associated neurocognitive disorder; Health; Human; Immune; Immune response; Impaired cognition; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Type II; Interferon alpha; Interleukin 7 Receptor; Interleukin-6; Leukocytes; Life Expectancy; Link; Mediating; Neurocognitive Deficit; Neurons; Patients; Peptides; Persons; Phenotype; Plasma; Process; Production; Property; Receptor Up-Regulation; Recombinant Interferon Alfa; Residual state; Rest; Role; Shapes; Stimulus; Surface; System; T memory cell; T-Cell Activation; TLR7 gene; Testing; Tetrahydrocannabinol; Viral; Virion; antiretroviral therapy; blood-brain barrier crossing; cannabinoid treatment; chronic infection; cognitive function; cytokine; genetic signature; immune activation; immunoregulation; marijuana user; microbial; migration; monocyte; neuroinflammation; neurotoxic; novel; receptor upregulation; recruit; response; uptake

PROJECT SUMMARY 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 disorders (HAND). A key event leading to HAND is persistent low-level chronic neuroinflammation 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. Activated, CD16+ monocytes are infected by HIV in the periphery and migrate across the blood-brain barrier (BBB) to release HIV virions and neurotoxic and proinflammatory factors. Before entering the CNS, resting (CD16–) monocytes transition into the CD16+ through poorly understood mechanisms including elevated interferon alpha (IFNα), a potent antiviral cytokine produced by plasmacytoid dendritic cells (pDC), an observation consistent with the IFNα gene signature in monocytes from HIV patients. Chronic IFNα production in HIV patients has been linked to neurocognitive impairment. In parallel, IFNα also activates CD8+ T cells, which are recruited from systemic circulation to cross the BBB. Once in the perivascular space, activated monocytes and CD8+ T cells interact with astrocytes to drive a chronic neuroinflammatory response leading to destruction of neurons and declining cognative function. Interestingly, cannabis, which has constituents (e.g., Δ9-tetrahydrocannabinol (THC)) possessing immune suppressive and anti-inflammatory activity, is widely used (approximately 25-37%) by HIV patients. The beneficial vs. deleterious effects of cannabinoid therapy in HIV patients remains unknown and understudied. Preliminary results show that THC suppresses IFNα-mediated CD16– to CD16+ monocyte transition as well as IL-7 receptor upregulation on CD8+ T cells. Moreover, HIV+ marijuana-users (MJ+) have fewer circulating CD16+ monocytes compared to HIV+MJ-. Preliminary data is also presented using a novel all human coculture system demonstrating that both monocytes and CD8+ T cells, when cocultured with astrocytes significant drive the secretion of astrocyte-derived inflammatory mediators, including IL-6 and IP-10, a response suppressed by THC. Mechanistic studies are proposed to test the hypothesis: Cannabinoids suppress interferon-α-mediated monocyte and CD8+ T cell activation in the periphery and their detrimental effects on astrocyte function, all of which are key processes in HIV-associated chronic neuroinflammation.

项目总结

项目成果

Immunomodulation by cannabinoids: Current uses, mechanisms, and identification of data gaps to be addressed for additional therapeutic application.

• DOI: 10.1016/bs.apha.2021.01.001
• 发表时间: 2021
• 期刊: Advances in pharmacology
• 作者: N. Kaminski;B. Kaplan

The current understanding of the benefits, safety, and regulation of cannabidiol in consumer products.

• DOI: 10.1016/j.fct.2021.112600
• 发表时间: 2021-11
• 期刊: FOOD AND CHEMICAL TOXICOLOGY
• 影响因子: 4.3
• 作者: Li, Jinpeng;Carvajal, Ricardo;Bruner, Leon;Kaminski, Norbert E.
• 通讯作者: Kaminski, Norbert E.

Cannabidiol selectively modulates interleukin (IL)-1β and IL-6 production in toll-like receptor activated human peripheral blood monocytes.

• DOI: 10.1016/j.tox.2021.153016
• 发表时间: 2021-12
• 期刊: TOXICOLOGY
• 影响因子: 4.5
• 作者: Sermet, Sera;Li, Jinpeng;Bach, Anthony;Crawford, Robert B.;Kaminski, Norbert E.
• 通讯作者: Kaminski, Norbert E.