DAT-Psychostimulant mediated dopamine release increases macrophage IL-1beta production through NF-kB activation and inflammasome priming

DAT 精神兴奋剂介导的多巴胺释放通过 NF-kB 激活和炎症小体引发增加巨噬细胞 IL-1β 的产生

• 批准号: 9978381
• 负责人: Peter Jesse Gaskill
• 金额: $ 23.48万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978381
• 关键词: Acute; Affect; B-Cell Activation; Behavior; Binding; Biological Response Modifiers; Brain; Brain region; CXCL10 gene; Cells; Central Nervous System Agents; Central Nervous System Diseases; Cerebrovascular Disorders; Cocaine; Cocaine Abuse; Complex; Corpus striatum structure; Data; Development; Dopamine; Dopamine Receptor; Drug abuse; Drug usage; Enhancers; Exposure to; Future; Gene Expression; Gene Proteins; Genes; HIV; Health; Hepatitis C virus; Human; IKK alpha; IL8 gene; Image; Immune; Incidence; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-6; Kinetics; Leukocytes; Light; Link; MAP3K7 gene; Maintenance; Mediating; Methamphetamine; Microarray Analysis; Microglia; Molecular; Multiprotein Complexes; Myelogenous; Myeloid Cells; NF-kappa B; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Nuclear; Nuclear Translocation; Nucleus Accumbens; Outcome; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Population; Prefrontal Cortex; Production; Proteins; Publishing; Research; Risk; Rodent Model; Role; Signal Transduction; Small Interfering RNA; Stimulus; System; Techniques; Therapeutic; Transcriptional Activation; Western Blotting; addiction; chromatin immunoprecipitation; cocaine use; cytokine; dopamine system; drug abuser; experimental study; extracellular; improved; knock-down; macrophage; marenostrin; methamphetamine use; monocyte; motor disorder; nervous system disorder; neuroinflammation; neuropathology; neuropsychiatric disorder; non-drug; novel; pathogenic bacteria; prevent; psychostimulant; receptor; recruit; response; scaffold; stimulant abuse; stimulant use; therapeutic target; transcription factor

DAT18-01. Abuse of stimulants, such as cocaine and methamphetamine, results in a variety of serious health conditions, and drug abusers have poorer health outcomes than non-drug using, demographically similar populations. In the central nervous system, the use of stimulants induces neuroinflammation through a greater release of inflammatory factors and recruitment of additional leukocytes. This predisposes drug abusers to a higher incidence of neuropsychiatric, cerebrovascular and motor disorders, and can also exacerbate the neuropathogenic impact of infection with HIV, HCV and a number of bacterial pathogens. The precise pathways by which stimulants mediate these effects are not clear, but many of these effects could be induced by drug-associated activation of specific inflammatory triggers such as NF- kB. However, direct links between stimulants and these neuroinflammatory mechanisms have not been described. The premise of this proposal is that dopamine acts as a common mechanism by which stimulants activate myeloid cell NF-kB and thereby initiate or exacerbate neuroinflammation. Use of all stimulants acutely increases CNS dopamine levels, exposing cells in dopamine-rich brain regions to aberrantly high dopamine concentrations. Among these cell populations are myeloid cells, such as perivascular macrophages and microglia, which are the primary immune cells in the CNS. Our published research shows that acute exposure to elevated dopamine increases myeloid production of inflammatory cytokines, such as IL-1b, IL-6, CXCL8 and CXCL10. Our preliminary data suggest that dopamine acts by activating the NF- kB pathway and priming the NLRP3 inflammasome, a complex that regulates the release of IL-1b, a master regulator of inflammation. The specific pathways mediating this effect are not clear, and therefore these studies will generate detailed information about specific dopamine receptors, gene and protein targets mediating dopamine activation of NF-kB and NLRP3 in human macrophages. Determining the specific signaling mechanisms and genes involved in dopamine induced increases in NF-kB activity will indicate pathways that could be targeted to ameliorate the neuroinflammatory effects of stimulant use, significantly improving the long-term health outcomes of stimulant users. The data developed in this proposal will serve as a basis for future projects examining the modulation of the myeloid dopaminergic system as a therapeutic strategy for limiting the increased incidence of neurologic disease and inflammation associated with drug abuse. These projects will examine both novel effectors and the repurposing of existing dopaminergic therapeutics to ameliorate inflammation in the stimulant abusing population.

DAT18-01。滥用兴奋剂，如可卡因和甲基苯丙胺，导致各种 严重的健康状况，吸毒者的健康结果比不吸毒者更差， 人口统计上相似的人群。在中枢神经系统中，兴奋剂的使用会诱导 通过更大程度地释放炎症因子和招募更多的 白细胞。这使吸毒者容易患上更高的神经精神疾病， 脑血管和运动障碍，也可加剧神经致病的影响 感染艾滋病毒、丙型肝炎病毒和一些细菌病原体。准确的路径，通过它 兴奋剂介导这些效应尚不清楚，但许多这些效应可能是由 药物相关的特定炎症因子的激活，如核因子-kB。然而，直接联系 兴奋剂和这些神经炎症机制之间的关系还没有被描述。这个 这一提议的前提是多巴胺作为一种共同的机制 兴奋剂激活髓系细胞核因子-kB，从而启动或加剧 神经炎。所有兴奋剂的使用都会显著增加中枢多巴胺水平，使细胞暴露 在多巴胺丰富的大脑区域，导致异常高的多巴胺浓度。在这些细胞中 人群是髓系细胞，如血管周围巨噬细胞和小胶质细胞，这是 中枢神经系统中的初级免疫细胞。我们发表的研究表明，急性暴露于高水平的 多巴胺促进髓系细胞产生炎性细胞因子，如IL-1b、IL-6、CXCL8 和CXCL10。我们的初步数据表明，多巴胺通过激活核因子-kB途径发挥作用 并启动NLRP3炎症体，这是一种调节IL-1b释放的复合体，是一种主要的 炎症调节剂。调节这一效应的具体途径尚不清楚，因此 这些研究将产生关于特定多巴胺受体、基因和 介导多巴胺激活的蛋白质靶点 核因子-kB 和NLRP3在人巨噬细胞中的表达。 确定多巴胺诱导的特定信号机制和基因 核因子-kB活性的增加将表明可以靶向改善 使用兴奋剂的神经炎症效应，显著改善长期健康结果 兴奋剂使用者。本提案中开发的数据将作为未来项目的基础 研究髓系多巴胺能系统的调节作为一种治疗策略 限制与药物有关的神经系统疾病和炎症的增加 虐待。这些项目将研究新的效应器和现有的 多巴胺能疗法减轻兴奋剂滥用人群的炎症反应。