Inter- and Intra-cellular effects of cannabinoids, HIV and ART in the CNS

大麻素、HIV 和 ART 对中枢神经系统的细胞间和细胞内影响

• 批准号: 10618933
• 负责人: Kelly L Jordan-Sciutto
• 金额: $ 69.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618933
• 关键词: Anti-Inflammatory Agents; Anti-Retroviral Agents; Antiinflammatory Effect; Anxiety; Astrocytes; Attenuated; CNR1 gene; Cannabinoids; Cannabis; Cell Lineage; Cells; Central Nervous System; Central Nervous System Diseases; Chronic; Colitis; Colon; Complex; Dendritic Cells; Disease; Dissection; Drug Side Effects; Environment; Exhibits; Experimental Autoimmune Encephalomyelitis; Functional disorder; Gene Expression; Gene Expression Profile; HIV; HIV Infections; Heart; Human; Immunomodulators; Inflammasome; Inflammation; Inflammatory; Kidney; Kinetics; Life Expectancy; Liver; Macrophage; Medicine; Mental Depression; Microglia; Modeling; Morphology; Myelogenous; Myocardial Infarction; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Oxidative Stress; Pain; Pathway interactions; Patients; Pattern; Persons; Production; Property; Reporting; Role; Signal Pathway; Signal Transduction; Stress; T-Lymphocyte; Tissues; Viral; antiretroviral therapy; anxiety reduction; biological adaptation to stress; body system; comorbidity; cytokine; experience; fetal; glial activation; immunoregulation; induced pluripotent stem cell; marijuana use; painful neuropathy; phytocannabinoid; pleasure; receptor; side effect

Abstract: Antiretroviral therapy (ART) has dramatically extended the lives of people living with HIV (PLWH); however, they continue to experience a plethora of co-morbid conditions including neuronal disorders and pain. Between 40 and 72% of PLWH use cannabis to mitigate anxiety, stress, ART side effects, pain, and/or for pleasure with over 55% of patients using cannabis at least daily. Interestingly, a recent study found that people who use cannabis heavily had reduced inflammatory signatures in PLWH on ART. These and a numerous other studies support the anti-inflammatory and immunomodulator effects of phytocannabinoids in a number of organ systems including heart, colon, kidney, liver and the gut; however, their medicinal use is confounded by the psychotropic activities. Efforts to separate the anti-inflammatory effects from the psychotropic effects have revealed differential activities of 3 endogenous receptors including cannabis receptor 1 (CB2) CB2 which exhibit differential tissue expression and agonism with endo- and phyto-cannabinoids. Several reports have shown that cannabinoids attenuate HIV infection and/or replication in T-cells, macrophages, dendritic cells and human fetal microglia cultured ex vivo. However, the effect of cannabinoids on HIV infection of microglia in the context of ART and the normal cellular environment of neighboring neurons and astrocytes in the CNS has not been examined. Several studies specifically implicate CB2 agonism which has been shown to have anti- inflammatory properties in the heart, gut, experimental autoimmune encephalitis and neuropathic pain via inflammasome activation. This has led us to hypothesize that Cannabinoid signaling influences HIV infection and chronic inflammation in the presence of ARV in the central nervous system by attenuating the inflammasome. In order to examine HIV infection in the context of cells of the CNS, we have developed a human induced pluripotent stem cell tri-culture model composed of iNeurons, iAstrocytes, and iMicroglia. This model recapitulates several key aspects of HIV infection in the CNS including increased cytokine production, oxidative stress response, inflammatory signaling, and integrated stress response. ARV treatment reduces HIV infection and inflammatory signaling pathways; however, a subset of pathways remain elevated despite viral suppression. We propose to further develop this model to determine the ability of cannabinoids to modulate HIV-induced inflammation and subsequent neuronal dysfunction via reducing inflammasome activation by: 1) Determining the effect of cannabinoids on chronic HIV infection and ART in the context of iMgl/iNrn/iAstr triculture. 2) Determining the effect of cannabinoids on cytokine levels, inflammatory gene expression profile, and microglial activation in iMgl/iNrn/iAstr triculture. 3) Determining the effect of cannabinoids on neurons and astrocytes in HIV infection and ART in iMgl/iNrn/iAstr triculture.

摘要： 抗逆转录病毒疗法（ART）极大地延长了艾滋病毒感染者（PLWH）的生命;然而， 他们继续经历过多的共病状况，包括神经元紊乱和疼痛。 40%至72%的PLWH使用大麻来减轻焦虑，压力，ART副作用，疼痛和/或 超过55%的患者至少每天使用大麻。有趣的是，最近的一项研究发现， 大量使用大麻的人在ART上减少了PLWH的炎症特征。 其他研究支持植物大麻素在许多疾病中的抗炎和免疫调节作用， 器官系统，包括心脏、结肠、肾脏、肝脏和肠道;然而，它们的药用受到以下因素的混淆： 精神活动。努力将抗炎作用与精神作用分开， 揭示了3种内源性受体的不同活性，包括大麻受体1（CB 2）CB 2， 表现出不同的组织表达和对内源性和植物性大麻素的激动作用。一些报道 表明大麻素减弱了HIV感染和/或T细胞、巨噬细胞、树突细胞和 体外培养人胎儿小胶质细胞。然而，大麻素对艾滋病毒感染的小胶质细胞的影响， ART的背景和CNS中邻近神经元和星形胶质细胞的正常细胞环境没有 被检查过了几项研究特别涉及CB 2激动作用，已显示其具有抗- 炎症性质的心脏，肠道，实验性自身免疫性脑炎和神经性疼痛， 炎性小体激活。这使我们假设大麻素信号影响HIV感染 和中枢神经系统中存在ARV时的慢性炎症，通过减弱 炎性小体 为了在CNS细胞的背景下检查HIV感染，我们已经开发了一种人源化的人源化的CNS细胞。 由iNeurons、iAstrocytes和iMicroglia组成的诱导多能干细胞三培养模型。该模型 概括了CNS中HIV感染的几个关键方面，包括细胞因子产生增加， 氧化应激反应、炎症信号传导和综合应激反应。抗逆转录病毒治疗减少 HIV感染和炎症信号传导途径;然而，尽管如此， 病毒抑制我们建议进一步开发这个模型，以确定大麻素的能力， 通过减少炎性小体调节HIV诱导的炎症和随后的神经元功能障碍 通过以下方式激活：1）在以下情况下确定大麻素对慢性HIV感染和ART的影响： iMgl/iNrn/iAstr triculture. 2)确定大麻素对细胞因子水平、炎症基因 表达谱和iMgl/iNrn/iAstr培养中的小胶质细胞活化。3)确定影响 大麻素对HIV感染中的神经元和星形胶质细胞以及iMgl/iNrn/iAstr培养中的ART的影响。

项目成果

HIV-Associated Insults Modulate ADAM10 and Its Regulator Sirtuin1 in an NMDA Receptor-Dependent Manner.

• DOI: 10.3390/cells11192962
• 发表时间: 2022-09-22
• 期刊: CELLS
• 影响因子: 6
• 作者: Lloreda, Claudia Lopez;Chowdhury, Sarah;Ghura, Shivesh;Alvarez-Periel, Elena;Jordan-Sciutto, Kelly
• 通讯作者: Jordan-Sciutto, Kelly

Confound, Cause, or Cure: The Effect of Cannabinoids on HIV-Associated Neurological Sequelae.

• DOI: 10.3390/v13071242
• 发表时间: 2021-06-26
• 期刊: Viruses
• 作者: Starr A;Jordan-Sciutto KL;Mironets E
• 通讯作者: Mironets E