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: 10612471
• 负责人: Norman J Haughey
• 金额: $ 56.96万
• 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/10612471
• 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; IL18 gene; Impaired cognition; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Intoxication; Learning; Leucine-Rich Repeat; Liver; Memory; Memory impairment; Metabolism; Microglia; Modification; Morphine; Mus; Neurons; Nucleotides; Opioid; Pathway interactions; Pattern recognition receptor; Persons; Phagocytosis; Pharmaceutical Preparations; Physiological; Population; Primary Cell Cultures; Proteins; Reactive Oxygen Species; Role; Self Administration; Synapses; System; Testing; Transgenic Mice; Transgenic Organisms; United States; Viral; Virus Diseases; biological adaptation to stress; cognitive function; complement system; cytokine; density; drug withdrawal; extracellular vesicles; fentanyl self-administration; 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. .

摘要 与未感染艾滋病毒的人群相比，艾滋病毒感染者（PLWH）的吸毒成瘾率更高， 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。 我们以前已经证明，急性吗啡给药引起的突触损伤， 戒毒期间的治疗这些修复机制在gp120转基因小鼠中并不活跃， 停药期间修复失败。尽管这些观察结果加上其他一些研究， 已经证明吗啡与HIV的相互作用最终会降低树突棘密度， 这些相互作用的机制尚不清楚。我们的初步发现表明最初的树突状细胞 吗啡诱导的损伤涉及非典型核苷酸结合寡聚化结构域的激活， 星形胶质细胞中富含亮氨酸的重复序列和含Pyrin结构域（NLRP）的炎性体通路， 携带补体C3的EV的释放。这种补体蛋白在树突棘和靶标中被调理 它们通过吞噬作用消除。吗啡的去除阻止了补体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， 小胶质细胞上模式识别受体的激活与经典NLRP的慢性激活 炎性体途径，维持持续炎症状态，这种慢性炎症状态 阻止树突棘自我修复在这里，我们建议使用原代细胞培养，EcoHIV感染的小鼠， 条件性转基因系统，以检验TLR、炎性小体和 补体系统参与阿片类药物滥用者的神经元损伤。 .

项目成果

Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV.

中性鞘磷脂酶2抑制作用减轻细胞外囊泡的释放，并改善鼠HIV中的神经行为缺陷。

• DOI: 10.1016/j.nbd.2022.105734
• 发表时间: 2022-07
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Zhu, Xiaolei;Hollinger, Kristen R.;Borjabad, Alejandra;Kim, Boe-Hyun;Arab, Tanina;Thomas, Ajit G.;Moniruzzaman, Mohammed;Lovell, Lyndah;Turchinovich, Andrey;Witwer, Kenneth W.;Volsky, David J.;Haughey, Norman J.;Slusher, Barbara S.
• 通讯作者: Slusher, Barbara S.