NLRP inflammasome directed activation of the innate immune system produces synaptic damage in EcoHIV infected mice self-administering fentanyl

NLRP 炎性体定向激活先天免疫系统，在 EcoHIV 感染小鼠自我施用芬太尼时产生突触损伤

• 批准号: 10085923
• 负责人: Norman J Haughey
• 金额: $ 47.26万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10085923
• 关键词: Acute; Adherence; Anti-Retroviral Agents; Astrocytes; Binding; Biogenesis; Biological Models; Brain; Capsid Proteins; Cessation of life; Chronic; Complement; Complex; Corpus striatum structure; Dendritic Spines; Disease Progression; Drug Addiction; Epidemic; Excision; Fentanyl; General Population; HIV; HIV Envelope Protein gp120; Heroin; Impaired cognition; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Interleukin-18; Intoxication; Learning; Leucine-Rich Repeat; Liver; Memory; Memory impairment; Metabolism; Microglia; Modification; Morphine; Mus; Neurons; Nucleotides; Opioid; Pathway interactions; Pattern recognition receptor; Phagocytosis; Pharmaceutical Preparations; Physiological; Population; Primary Cell Cultures; Proteins; Reactive Oxygen Species; Role; Self Administration; Synapses; System; Testing; Transgenic Mice; Transgenic Organisms; United States; Up-Regulation; Viral; Virus Diseases; biological adaptation to stress; cognitive function; complement system; cytokine; density; drug withdrawal; extracellular vesicles; immune function; improved; in vivo Model; marenostrin; morphine administration; neuron loss; opioid abuse; opioid use; opioid withdrawal; oxidation; prevent; repaired; response; tat Protein

ABSTRACT People living with HIV (PLWH) have higher rates of drug addiction compared with uninfected populations, and often show faster rates of disease progression, including early and rapidly progressing cognitive impairments. We have previously demonstrated that synaptic damage resulting from acute morphine administration self- repairs during drug withdrawal. These repair mechanisms were not active in gp120 transgenic mice, and synaptic repair failed during drug withdrawal. Although these observations in addition to a number of other studies that have demonstrated interactions of morphine with HIV that ultimately reduce dendritic spine density, the precise mechanisms for these interactions are not understood. Our preliminary findings suggests that the initial dendritic damage induced by morphine involves activation of a non-canonical Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing (NLRP) inflammasome pathway in astrocytes that facilitates the release of EVs carrying complement C3. This complement protein is opsonized in dendritic spines and targets them for elimination by phagocytosis. The removal of morphine stops the shedding of complement C3 from astrocytes, and dendritic spines can self-repair. However, in the setting of viral infection there is a sustained activation of pattern recognition receptors on microglia with chronic activation of the classical NLRP inflammasome pathway that maintains a state of persistent inflammation, This chronic inflammatory state disallows dendritic spines to self-repair. Here we propose to use primary cell culture, EcoHIV infected mice, and conditional transgenic systems to test the hypothesis that interactions between TLRs, the inflammasome, and the complement system contribute to neuronal damage in PLHW who abuse opiates. .

抽象的 与未感染人群相比，艾滋病毒感染者 (PLWH) 吸毒成瘾的比例更高，并且 通常表现出更快的疾病进展速度，包括早期和快速进展的认知障碍。 我们之前已经证明，急性吗啡给药导致的突触损伤是自我修复的。 停药期间进行修复。这些修复机制在 gp120 转基因小鼠中不活跃，并且突触 停药期间修复失败。尽管这些观察结果加上许多其他研究表明 已经证明吗啡与 HIV 相互作用，最终降低树突棘密度，精确的 这些相互作用的机制尚不清楚。我们的初步研究结果表明，最初的树突 吗啡引起的损伤涉及非典型核苷酸结合寡聚结构域的激活， 星形胶质细胞中富含亮氨酸的重复序列和含有 Pyrin 结构域 (NLRP) 的炎症小体通路，促进 携带补体 C3 的 EV 的发布。这种补体蛋白在树突棘和靶标中被调理 它们通过吞噬作用被消除。吗啡的去除会阻止补体 C3 的脱落 星形胶质细胞和树突棘可以自我修复。然而，在病毒感染的情况下，存在持续的 小胶质细胞上模式识别受体的激活伴随经典 NLRP 的慢性激活 维持持续炎症状态的炎症小体途径，这种慢性炎症状态 不允许树突棘自我修复。在这里，我们建议使用原代细胞培养物、EcoHIV 感染小鼠，以及 条件转基因系统来检验 TLR、炎性体和 TLR 之间相互作用的假设 补体系统会导致滥用阿片类药物的艾滋病患者的神经元损伤。 。