AIM(2)ing at the inflammasome: Impact of MAVS signaling in cocaine-and HIV-1 induced neuroinflammation

AIM(2)ing 作用于炎症小体：MAVS 信号传导对可卡因和 HIV-1 诱导的神经炎症的影响

• 批准号: 10574501
• 负责人: Irma Cisneros
• 金额: $ 59.39万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574501
• 关键词: AIM2 gene; Address; Antioxidants; Antiviral Response; Astrocytes; Attenuated; Binding; CASP1 gene; Caspase; Central Nervous System Diseases; Chronic; Cocaine; Development; Disease Progression; Equilibrium; Event; Failure; Flavonoids; Future; Generations; Genes; HIV; HIV-1; HIV-associated neurocognitive disorder; Immune response; Immunologics; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferons; Intervention; Measures; Mediating; Mitochondria; Outcome; Pathogenicity; Pathology; Pattern recognition receptor; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Play; Production; Protein Inhibition; Proteins; Proteolysis; Quercetin; Recurrence; Regulation; Reporting; Response Elements; Risk; Role; Severities; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Testing; Toxic effect; United States; Viral; Viral Physiology; antiviral immunity; chemokine; cocaine exposure; comorbidity; cytokine; drug of abuse; neuroinflammation; neurotoxicity; novel; protein activation; protein aggregation; protein function; receptor; recruit; scaffold; tissue injury

Project Summary/Abstract Cocaine, the second highest used illegal drug in the US, reduces CNS immune responses to HIV-1, increasing the severity and onset of HIV-1-mediated neurotoxicity. Astrocytes are the first line of defense against toxicity in the CNS and initiate inflammatory responses to HIV-1 and antiviral activity following cocaine exposure (33); however, uncontrolled inflammation and the failure to control HIV-1 replication is a continued problem. Mitochondrial antiviral signaling protein (MAVS), together with absent in melanoma 2 (AIM2)-like receptor inflammasomes, their interactions, crosstalk and dual scaffolding could be key mechanisms triggering inflammatory and antiviral signaling in cocaine and HIV-1. Cocaine exposure in astrocytes, increases interferons (IFNs) (33) and activity of the IFN stimulated response element (ISRE), presumably via MAVS. We identified that cocaine induced mitochondrial toxicity, which regulates MAVS function and AIM2 inflammasome activation (30, 77). We discovered that cocaine exposure in astrocytes is a major regulator of AIM2 priming measured by increased caspase-1 cleavage and AIM2 levels, an IFN stimulated gene (ISG) (32, 88). Furthermore, MAVS plays a crucial role in cocaine induced AIM2 priming as demonstrated in MAVS downregulated astrocytes. Dual overactivation of MAVS and AIM2 produce chronic inflammatory pathologies, via NFκB signaling and IFN production (16, 23). We established that repeated cocaine exposure reduced MAVS cleaved products and increased MAVS aggregation, which differentially dictate IFN and NFκB signaling, and we measured increased cytokines/chemokines and decreased IFNβ. Interestingly, AIM2 binding partner, adaptor associated speck-like protein (ASC), binds MAVS via caspase recruitment domain (CARD)-CARD homotypic interactions to inhibit MAVS-induced IFN generation (35). ASC is regulated by kinases initiated by MAVS and IFN signaling (36, 37) and may play a vital role in promoting AIM2-induced aberrant neuroinflammation and reduced MAVS antiviral signaling, in cocaine and HIV-1. We hypothesize that cocaine promotes MAVS activation via mitochondrial toxicity, priming AIM2 inflammasomes. Repeated cocaine exposure, and/or HIV-1, results in dual recruitment of ASC to astrocyte MAVS/AIM2. ASC recruitment initiates signal transduction events triggering astrocyte- induced inflammation and decrease antiviral signaling, promoting astrocyte-induced neurotoxicity in cocaine and HIV-1. To test this hypothesis we will uncover mechanisms by which cocaine cause AIM2 inflammasome priming via astrocyte MAVS activation (Aim 1); delineate astrocyte MAVS and AIM2 scaffolding and crosstalk on AIM2 inflammasome oligomerization and signaling (Aim 2); and explore the impact of astrocyte ASC regulation/recruitment in AIM2 signaling and attenuated MAVS activation in cocaine and HIV-1. Repeated cocaine exposure, and/or subsequent introduction of HIV-1, inundates the innate immune response producing a hyperimmuno and decreased antiviral phenotype, increasing the risk of HIV-1 neurotoxicity.

项目摘要/摘要 可卡因是美国第二高使用的非法药物，将CNS免疫调查降低到HIV-1，增加 HIV-1介导的神经毒性的严重程度和发作。星形胶质细胞是对毒性的第一道防线 在中枢神经系统中，可卡因暴露后对HIV-1和抗病毒活性产生炎症反应（33）； 但是，不受控制的注射和无法控制HIV-1复制是一个持续的问题。 线粒体抗病毒信号传导蛋白（MAV），黑色素瘤2（AIM2）类似接收器 炎症，它们的相互作用，串扰和双脚手架可能是触发的关键机制 可卡因和HIV-1的炎症和抗病毒信号传导。星形胶质细胞中的可卡因暴露，增加 干扰素（IFNS）（33）和IFN刺激响应元件（ISRE）的活性，大概是通过MAVS。我们 确定可卡因诱导线粒体毒性，从而调节MAV功能和AIM2炎症体 激活（30，77）。我们发现，星形胶质细胞中的可卡因暴露是AIM2启动的主要调节剂 通过增加的caspase-1裂解和AIM2水平测量，IFN刺激基因（ISG）（32，88）。 此外，MAVS在可卡因诱导的AIM2启动中起着至关重要的作用 星形胶质细胞下调。 MAV和AIM2的双重活化产生了慢性炎症性病理， 通过NFκB信号传导和IFN产生（16，23）。我们确定重复可卡因的暴露减少了 MAVS裂解产物并增加了MAV的聚集，这决定了IFN和NFκB信号的不同， 我们测量了细胞因子/趋化因子的增加，并改善了IFNβ。有趣的是，AIM2约束伙伴， 适配器相关规格样蛋白（ASC），通过caspase募集域（卡）绑定MAV 同种型相互作用以抑制MAVS诱导的IFN产生（35）。 ASC由由 MAV和IFN信号传导（36，37），可能在促进AIM2诱导的异常中起着至关重要的作用 可卡因和HIV-1中的神经炎症和降低的MAV抗病毒信号传导。 我们假设可卡因通过线粒体毒性促进MAV激活 AIM2炎症。重复的可卡因暴露和/或HIV-1导致ASC双重募集到 星形胶质细胞小牛/AIM2。 ASC募集启动信号传输事件触发星形胶质细胞 - 诱导炎症并减少抗病毒信号传导，促进星形胶质细胞引起的神经毒性 可卡因和HIV-1。为了检验这一假设，我们将发现可卡因引起AIM2的机制2 通过星形胶质细胞MAV激活炎症体启动（AIM 1）；描绘星形胶质细胞小牛和AIM2脚手架 在AIM2炎性体的低聚和信号传导上串扰（AIM 2）；并探索 AIM2信号传导中的星形胶质细胞ASC调节/募集，可卡因和HIV-1中的MAVS激活。 重复可卡因暴露和/或随后引入HIV-1，淹没了先天免疫反应 产生超木并改善抗病毒表型，从而增加了HIV-1神经毒性的风险。