Role of the NLRP3 Inflammasome in Mediating Microglial Activation and Development of Neuropsychiatric Symptoms Induced by HIV, Antiretrovirals and Cocaine

NLRP3 炎症小体在介导小胶质细胞激活和 HIV、抗逆转录病毒药物和可卡因诱导的神经精神症状发展中的作用

• 批准号: 10326539
• 负责人: Minglei Guo
• 金额: $ 38.47万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10326539
• 关键词: Adult; Affect; Anti-Retroviral Agents; Anxiety; Archives; Autopsy; Behavior; Behavioral; Biological Response Modifiers; Brain; Brain region; Cell Nucleus; Chronic; Cocaine; Cocaine Abuse; Coculture Techniques; Data; Development; Doxycycline; Drug abuse; Excision; Functional disorder; Genetic Transcription; Glutamate Receptor; HIV; HIV Infections; HIV Seronegativity; HIV antiretroviral; High Prevalence; Human; IL18 gene; Immune response; In Vitro; Incidence; Individual; Inflammasome; Inflammatory; Interleukin-1 beta; Label; Life Expectancy; Lysosomes; Macaca; Mediating; Mental Depression; Microglia; Morphology; Mus; N-Methylaspartate; Neurologic; Neuronal Injury; Pathologic; Pathway interactions; Population; Prevalence; Process; Production; Proteins; Quality of life; Regulation; Risk Factors; Role; SIV; Signal Transduction; System; TLR4 gene; Tenofovir; Testing; Therapeutic Effect; Therapeutic Intervention; Trans-Activators; Transcription Coactivator; Vertebral column; antiretroviral therapy; base; brain tissue; clinical practice; cocaine self-administration; cocaine use; comorbidity; density; drug of abuse; emtricitabine; experimental study; in vivo; inhibitor/antagonist; marenostrin; nervous system disorder; neuropsychiatric disorder; neuropsychiatric symptom; neuropsychiatry; neurotoxicity; peer; tat Protein; therapeutically effective

Abstract Although people living with HIV (PLWHIV) have comparable life-expectancy as the HIV-negative population does, their life-quality is still deeply compromised due to the prevalence of neuropsychiatric disorders including depression and anxiety. The main pathological changes in the brains of those people include aberrant microglial (Mg) activation and neuronal injuries. Drug abuse is a high comorbidity of HIV infection and abused drugs could exaggerate the existing neurologic complications in PLWHIV. The detailed mechanisms underlying such phenomenon remain much elusive. Several contributing factors have been suggested for such neurological disorders including the continued expression HIV proteins such as trans-activator of transcription (TAT), the long-term use of antiretrovirals (ARVs), and drugs of abuse. Our preliminary data demonstrated that :1) NLRP3 inflammasome signaling was involved in HIV-TAT-mediated Mg activation; 2) cocaine activated Mg through dysregulating miR-124/TLR4 axis, which could be reversed by inhibition of NLRP3 inflammasome; 3) combination ARVs used in clinical practice (tenofovir:TFV, emtricitabine:FTC, and dolutegravir:DTG) could activate Mg via lysosomal dysfunction; 4) co-exposure of Mg to three agents (TAT, cocaine, and ARVs) intriguingly resulted in increased activity of NLRP3 inflammasome in vitro; 5) IL1β, the final executor of NLRP3 inflammasome activation, decreased the spine density and increase the glutamate receptor ionotropic NMDA subunits (Grins) in vitro; and 6) increased NLRP3 inflammasome activity was shown in the brains of SIV-infected macaque. Based on these findings and two distinct steps of NLRP3 inflammasome activation, we hypothesize that exacerbated NLRP3 inflammasome activation in the context of HIV-TAT/HIV, cocaine, ARVs will lead to exaggerated Mg activation and neuronal injuries, which are responsible for the high incidence of neuropsychiatric disorders in PLWHIV with cocaine use. We will test this hypothesis in the following two specific aims (SA) using complimentary in vitro and in vivo approaches. SA1: Investigate the role of NLRP3 inflammasome in Mg activation and neuronal injuries in the context of HIV-TAT/HIV, cocaine, & ARVs. We will split this SA into three sub aims. SA1A will explore the detailed mechanisms responsible for exaggerated NLRP3 inflammasome activation in vitro; SA1B will explore the mechanisms underlying NLRP3 inflammasome-mediated neuronal injuries; and SA1C will investigate the status of NLRP3 inflammasome and neuronal injuries in archived SIV- infected macaque brains and HIV-infected individuas with or without cocaine use. SA2: Explore the potential therapeutic effects of NLRP3 inflammasome inhibition on neuropsychiatric behaviors in HIV iTat mice in vivo.

摘要 尽管艾滋病毒携带者(PLWHIV)的预期寿命与艾滋病毒阴性者相当 然而，由于神经精神疾病的流行，他们的生活质量仍然严重受损，包括 抑郁和焦虑。这些人大脑的主要病理变化包括异常的小胶质细胞。 (Mg)激活和神经元损伤。滥用药物是艾滋病毒感染的高度共病，滥用药物可能 夸大了PLWHIV现有的神经系统并发症。这种情况背后的详细机制 这一现象仍然很难捉摸。有几个因素被认为是导致这种神经病的原因 疾病包括艾滋病毒蛋白的持续表达，如反式转录激活因子(TAT)， 长期使用抗逆转录病毒药物(ARV)和滥用药物。我们的初步数据表明：1)NLRP3 炎症小体信号参与HIV-TAT介导的镁激活；2)可卡因通过 MiR-124/TLR4轴失调，抑制NLRP3炎症小体可逆转；3) 临床上使用的联合抗逆转录病毒药物(替诺福韦：TFV，恩曲他滨：FTC，多洛替格韦：DTG)可以 通过溶酶体功能障碍激活镁；4)镁与三种药物(TAT、可卡因和抗逆转录病毒药物)的联合暴露 耐人寻味地在体外导致NLRP3炎症体活性增加；5)NLRP3的最终执行者IL1β 炎性小体激活，降低脊髓密度，增加谷氨酸受体离子型NMDA 6)感染SIV的大鼠脑内NLRP3炎症体活性增强 猕猴。基于这些发现和NLRP3炎症小体激活的两个不同步骤，我们假设 这加剧了NLRP3炎症体的激活，在艾滋病毒-TAT/艾滋病毒、可卡因、抗逆转录病毒药物的背景下将导致 过度的镁激活和神经元损伤是神经精神疾病高发的原因 PLWHIV与可卡因使用有关的疾病。我们将在以下两个特定目标(SA)中使用 免费的体外和体内方法。SA1：研究NLRP3炎症体在MG中的作用 HIV-TAT/HIV、可卡因和抗逆转录病毒药物背景下的激活和神经元损伤。我们将把这个SA一分为三 潜射目标。SA1A将探索导致NLRP3炎症小体夸大的详细机制 体外激活；SA1B将探索NLRP3炎症小体介导的神经元的机制 SA1C将调查存档的SIV中NLRP3炎症体和神经元损伤的状况。 感染的猕猴大脑和感染艾滋病毒的个体使用或不使用可卡因。SA2：发掘潜力 NLRP3炎性小体抑制对HIV感染小鼠神经精神行为的治疗作用