EphB2-mediated ephrin-B reverse signaling on microglia drives an anti-viral, but inflammatory and neurotoxic response associated with HIV.

IF 10.1 1区 医学 Q1 IMMUNOLOGY
Jeffrey Koury, Hina Singh, Samantha N Sutley-Koury, Dominic Fok, Xinru Qiu, Ricky Maung, Benjamin B Gelman, Iryna M Ethell, Marcus Kaul
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引用次数: 0

Abstract

Background: Pathological inflammation with a loss of synaptic integrity and function has been implicated in HIV Associated Neurocognitive Disorders (HAND). Although therapeutics exist to increase the lifespan of people living with HIV (PLWH), they are not effective at preventing neuroinflammation and HIV induced neuronal damage persists. In this study, we investigate the ephrin-B/EphB axis, which regulates inflammation, in post-mortem brain specimen of PLWH and experimental models in order to assess its potential role in HIV induced neuroinflammation.

Methods: We analyze mRNA samples of post-mortem brain specimen of PLWH and uninfected controls obtained from the National NeuroAIDS Tissue Consortium (NNTC) and, for comparison, of a transgenic mouse model of neuroHIV using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Follow-up experiments employ mouse brain tissue and in vitro models, including immortalized human microglia, human induced pluripotent stem cell (iPSC)-derived mixed neuroglial cell cultures, cellular and molecular interference, functional and multiplex assays, immunofluorescence and mRNA sequencing to examine the role of the ephrin-B/EphB axis in neuroinflammation and the associated neurotoxicity.

Results: Using qRT-PCR we find increased expression of EphB2 in post-mortem brain of PLWH, and detect a correlation with pro-viral DNA, viral RNA and an inverse correlation with abstract executive function and verbal fluency. Increased expression of ephrin-B/EphB at mRNA and protein level is also observed in brains of a transgenic mouse model of neuroHIV suggesting the upregulation can be driven, at least in part, by expression of viral gp120 envelope protein and a type I interferon, IFNβ. Additionally, we find induction of ephrin-B1 expression in microglia following activation by IFNβ. Given the previously reported impact of EphB2 on inflammation in the periphery, the functional role of EphB2-mediated ephrin-B reverse signaling on microglia is assessed for a pro-inflammatory and anti-viral signature. We find that EphB2 treated microglia secrete inflammatory and anti-viral factors but also exert contact-independent neurotoxicity. Finally, knockdown of microglial ephrin-B1, an EphB2 binding partner, shows a partial alleviation of the microglial pro-inflammatory signature and neurotoxicity.

Conclusion: Our study suggests that elevated EphB2, and its reverse signaling through ephrin-B1 in microglia contribute to neuroinflammation and neurotoxicity in neuroHIV.

ephb2介导的小胶质细胞上的ephrin-B反向信号驱动与HIV相关的抗病毒,但炎症和神经毒性反应。
背景:具有突触完整性和功能丧失的病理性炎症与HIV相关神经认知障碍(HAND)有关。虽然现有的治疗方法可以延长艾滋病毒感染者的寿命,但它们在预防神经炎症方面并不有效,而且艾滋病毒诱导的神经元损伤仍然存在。在本研究中,我们研究了在PLWH死后脑标本和实验模型中调节炎症的ephrin-B/EphB轴,以评估其在HIV诱导的神经炎症中的潜在作用。方法:我们分析了从国家神经艾滋病组织联合会(NNTC)获得的PLWH死后脑标本和未感染对照的mRNA样本,并使用定量逆转录聚合酶链反应(qRT-PCR)对转基因小鼠神经hiv模型进行比较。后续实验采用小鼠脑组织和体外模型,包括永生化人小胶质细胞、人诱导多能干细胞(iPSC)衍生的混合神经胶质细胞培养、细胞和分子干扰、功能和多重检测、免疫荧光和mRNA测序,以检测ephrin-B/EphB轴在神经炎症和相关神经毒性中的作用。结果:采用qRT-PCR技术,我们发现phb2在PLWH死后脑组织中表达升高,并与前病毒DNA、病毒RNA呈相关,与抽象执行功能和语言流畅性呈负相关。在神经hiv转基因小鼠模型的大脑中也观察到ephrin-B/EphB在mRNA和蛋白水平上的表达增加,这表明这种上调可能至少部分是由病毒gp120包膜蛋白和I型干扰素IFNβ的表达驱动的。此外,我们发现在IFNβ激活后,小胶质细胞中诱导ephrin-B1的表达。鉴于先前报道的EphB2对外周炎症的影响,我们评估了EphB2介导的ephrin-B反向信号在小胶质细胞中的功能作用,以确定其促炎和抗病毒特征。我们发现EphB2可以治疗小胶质细胞分泌炎症和抗病毒因子,但也可以发挥不依赖接触的神经毒性。最后,敲低小胶质ephrin-B1 (EphB2的结合伙伴)显示了小胶质促炎特征和神经毒性的部分减轻。结论:我们的研究表明,EphB2的升高及其通过小胶质细胞ephrin-B1的反向信号通路参与了神经hiv的神经炎症和神经毒性。
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来源期刊
Journal of Neuroinflammation
Journal of Neuroinflammation 医学-神经科学
CiteScore
15.90
自引率
3.20%
发文量
276
审稿时长
1 months
期刊介绍: The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.
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