Release of Soluble Insulin Receptor From Neurons by Cerebrospinal Fluid From Patients With Neurocognitive Dysfunction and HIV Infection
Release of Soluble Insulin Receptor From Neurons by Cerebrospinal Fluid From Patients With Neurocognitive Dysfunction and HIV Infection
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DOI：
10.3389/fneur.2019.00285
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发表时间：
2019-03-26
影响因子：
3.4
通讯作者：
Wojna, Valerie
中科院分区：
文献类型：
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作者：
Gerena, Yamil;Menendez-Delmestre, Raissa;Wojna, Valerie
此前，我们发现HIV感染女性队列中脑脊液(CSF)中高水平的可溶性胰岛素受体(SIR)与HIV相关神经认知障碍(HAND)的存在和严重程度有关。在这项研究中，我们调查了这一人群的脑脊液(HIV-1TAT)和选定的细胞因子是否诱导人类神经细胞分泌SIR。对23名按认知状况分层的艾滋病毒血清阳性妇女和5名艾滋病毒血清阴性妇女进行了评估。测定暴露于患者脑脊液中的神经细胞(SH-SY5Y)细胞外培养上清液中的可溶性IR水平。采用酶联免疫吸附试验和流式细胞仪检测受试者脑脊液中SIR、HIV-1TAT和细胞因子(IL-2、IL-4、IL-6、干扰素-γ、肿瘤坏死因子-α和IL-10)水平。检测HIV1TAT(0.5-250 nM)或特定细胞因子作用24 h后神经元SIR的分泌。在R7050(肿瘤坏死因子α拮抗剂，10 nM)存在的情况下，还观察了肿瘤坏死因子α和HIV-1 TAT对SIR分泌的影响。根据参与者神经认知损害的严重程度，暴露在HIV感染女性脑脊液中的神经元具有更高的SIR水平。在有认知障碍的HIV感染妇女中，脑脊液SIR水平升高与手部的存在和严重程度相关，并与脑脊液HIV-1 TAT水平呈正相关。脑脊液中IL-2、干扰素-γ和肿瘤坏死因子-α水平显著升高。然而，只有肿瘤坏死因子α(5pg/mL)和HIV-1TAT(100 NM)在作用24小时后才能显著增加神经元SIR的分泌，当两者与R7050联合使用时，这种作用被拮抗。提示HIV感染者脑脊液中的肿瘤坏死因子α和HIV-1 TAT可能调节神经细胞分泌SIR，而HIV-1 TAT对SIR分泌的影响可能依赖于其受体的激活。
Previously, we found that high levels of soluble insulin receptor (sIR) in the cerebrospinal fluid (CSF) of an HIV-infected women cohort were associated with the presence and severity of HIV-associated neurocognitive disorders (HAND). In this study we investigated if CSF from this population, HIV-1 Tat, and selected cytokines induces sIR secretion from human neuronal cells. Twenty-three (23) HIV-seropositive women stratified by cognitive status and five HIV-seronegative women were evaluated. Soluble IR levels were measured in the extracellular medium of neuronal cells (SH-SY5Y) that were exposed (for 24 h) to the CSF of patients. The levels of sIR, HIV-1 Tat, and cytokine levels (IL-2, IL4, IL-6, IFN gamma, TNF alpha, and IL-10) were quantified in the CSF of participants by ELISA and flow cytometry. Neuronal secretion of sIR was measured after exposure (24 h) to HIV-1 Tat (0.5-250 nM), or specific cytokines. The effects of TNF alpha and HIV-1 Tat on sIR secretion were also evaluated in the presence of R7050 (TNF alpha antagonist; 10 nM). Neurons exposed to the CSF of HIV-infected women had higher sIR levels according to the severity of neurocognitive impairment of the participant. Increased CSF sIR levels were associated with the presence and severity of HAND and were positively correlated with CSF HIV-1 Tat levels in HIV-infected women with cognitive impairment. CSF levels of IL-2, IFN gamma g, and TNF alpha were significantly increased with HAND. However, only TNF alpha (5 pg/mL) and HIV-1 Tat (100 nM) induced a significant increase in neuronal sIR secretion after 24 h exposure, an effect that was antagonized when each were combined with R7050. Our data suggests that TNF alpha and HIV-1 Tat from the CSF of HIV-infected women may regulate the secretion of sIR from neuronal cells and that the effect of HIV-1 Tat on sIR secretion may depend on TNF alpha receptor activation.