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

摘要 艾滋病毒携带者(PLWH)与未感染人群相比，吸毒率更高，并且 通常表现出较快的疾病进展速度，包括早期和快速进展的认知障碍。 我们先前已经证明，急性吗啡给药导致的突触损伤是自体的。 戒毒期间的维修。这些修复机制在gp120转基因小鼠中并不活跃，并且突触 停药期间修复失败。虽然这些观察结果除了一些其他研究外， 已经证明了吗啡与HIV的相互作用最终会降低树突棘的密度， 这些相互作用的机制还不清楚。我们的初步发现表明，最初的树突 吗啡引起的损伤包括激活一个非规范的核苷酸结合寡聚化结构域， 星形胶质细胞富含亮氨酸重复序列和含有吡咯环的炎症体途径 携带补体C3的电动汽车的释放。这种补体蛋白在树突棘和靶体内被调理。 它们可以通过吞噬作用消除。去除吗啡可阻止补体C3从体内排出 星形胶质细胞和树突棘可以自我修复。然而，在病毒感染的背景下，有一种持续性的 经典NLRP慢性激活过程中小胶质细胞模式识别受体的激活 维持持续炎症状态的炎症体途径，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，EcoHIV感染的小鼠，以及 有条件的转基因系统，以测试TLRs、炎症体和 补体系统导致滥用阿片类药物的PLHW的神经元损伤。 。

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. .