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: 10371029
• 负责人: Irma Cisneros
• 金额: $ 61.12万
• 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/10371029
• 关键词: AIM2 gene; Address; Antioxidants; Antiviral Response; Astrocytes; Attenuated; Binding; Binding Proteins; 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; Lead; Measures; Mediating; Mitochondria; Outcome; Pathogenicity; Pathology; Pattern recognition receptor; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Play; Production; Protein Inhibition; Proteins; Proteolysis; Quercetin; Regulation; Reporting; Response Elements; Risk; Role; Severities; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Testing; Toxic effect; United States; 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.

项目概要/摘要 可卡因是美国使用量第二大的非法药物，它会降低中枢神经系统对 HIV-1 的免疫反应，从而增加 HIV-1 介导的神经毒性的严重程度和发作是抵抗毒性的第一道防线。 在中枢神经系统中，并在接触可卡因后引发对 HIV-1 的炎症反应和抗病毒活性 (33)； 然而，不受控制的炎症和无法控制 HIV-1 复制仍然是一个持续存在的问题。 线粒体抗病毒信号蛋白 (MAVS)，以及黑色素瘤 2 (AIM2) 样受体中缺失 炎症小体、它们的相互作用、串扰和双支架可能是触发的关键机制 星形胶质细胞中可卡因和 HIV-1 的炎症和抗病毒信号传导增加。 干扰素 (IFN) (33) 和 IFN 刺激反应元件 (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 MAVS 功能和 AIM2 炎性体 我们发现星形胶质细胞中的可卡因暴露是 AIM2 启动的主要调节因子。 通过增加 caspase-1 裂解和 AIM2 水平（一种 IFN 刺激基因 (ISG)）来测量 (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，如 MAVS 所示 MAVS 和 AIM2 的双重过度激活会产生慢性炎症病理， 通过 NFκB 信号传导和 IFN 产生 (16, 23)，我们确定反复接触可卡因会减少。 MAVS 裂解产物和增加的 MAVS 聚集，差异决定了 IFN 和 NFκB 信号传导， 我们测量了细胞因子/趋化因子的增加和 IFNβ 的减少。 接头相关斑点样蛋白 (ASC)，通过半胱天冬酶募集结构域 (CARD) 结合 MAVS-CARD 抑制 MAVS 诱导的 IFN 生成的同型相互作用受到由以下酶启动的激酶的调节 (35)。 MAVS 和 IFN 信号传导 (36, 37) 可能在促进 AIM2 诱导的异常中发挥重要作用 可卡因和 HIV-1 中的神经炎症和 MAVS 抗病毒信号减弱。 我们发现可卡因通过线粒体毒性促进 MAVS 激活，启动 AIM2 炎症小体反复接触可卡因和/或 HIV-1，导致 ASC 双重募集。 星形胶质细胞 MAVS/AIM2。ASC 募集启动信号转导事件，触发星形胶质细胞- 炎症诱导并减少抗病毒信号传导，促进星形胶质细胞诱导的神经毒性 为了检验这一假设，我们将揭示可卡因引起 AIM2 的机制。 通过星形胶质细胞 MAVS 激活引发炎症小体（目标 1）；描绘星形胶质细胞 MAVS 和 AIM2 支架； 和串扰对 AIM2 炎症小体寡聚化和信号转导（目标 2）的影响； AIM2 信号传导中星形胶质细胞 ASC 的调节/募集以及可卡因和 HIV-1 中 MAVS 激活的减弱。 反复接触可卡因和/或随后引入 HIV-1，会淹没先天免疫反应 产生过度免疫并降低抗病毒表型，增加 HIV-1 神经毒性的风险。