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。滥用可卡因和甲基苯丙胺等兴奋剂，导致多种 严重的健康状况和吸毒者的健康状况比非药物使用的健康结果差， 人口相似的人群。在中枢神经系统中，刺激剂的使用会诱导 通过更大的炎症因素释放并募​​集其他额外的神经炎症 白细胞。这使滥用药物易于神经精神病患者的发生率更高 脑血管和运动障碍，也可能加剧 HIV，HCV和许多细菌病原体感染。确切的途径 刺激剂介导这些效果尚不清楚，但是其中许多效果可能由 药物相关的特定炎症触发因素（如NF-KB）的激活。但是，直接链接 在兴奋剂和这些神经炎症机制之间尚未描述。这 该提议的前提是多巴胺是一种共同的机制 兴奋剂激活髓样细胞NF-KB，从而启动或加重 神经炎症。所有兴奋剂的使用敏锐地增加了CNS多巴胺水平，暴露了细胞 在多巴胺的大脑区域中，多巴胺浓度异常高。在这些细胞中 种群是髓样细胞，例如周围巨噬细胞和小胶质细胞，是 中枢神经系统中的原发性免疫细胞。我们发表的研究表明，急性暴露于升高 多巴胺增加炎性细胞因子的髓样产生，例如IL-1B，IL-6，CXCL8 和CXCL10。我们的初步数据表明，多巴胺通过激活NF-KB途径起作用 并启动NLRP3炎性体，该复合体调节IL-1B的释放，主人 炎症调节剂。介导这种效果的特定途径尚不清楚，因此 这些研究将产生有关特定多巴胺受体，基因和基因的详细信息 蛋白质靶向介导多巴胺激活的蛋白 NF-KB 和人类巨噬细胞中的NLRP3。 确定多巴胺诱导的特定信号传导机制和基因 NF-KB活性的增加将指示可以针对改善的途径 兴奋剂使用的神经炎症作用，显着改善了长期健康结果 兴奋的用户。本提案中开发的数据将作为未来项目的基础 研究髓样多巴胺能系统的调节作为一种治疗策略 限制与药物相关的神经系统疾病和炎症的发病率增加 虐待。这些项目将检查新颖的效应子和现有的重新使用 多巴胺能疗法可以改善刺激滥用人群的炎症。