Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics
Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics
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DOI：
10.1128/jvi.00603-16
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发表时间：
2016-08-01
影响因子：
5.4
通讯作者：
Fraternale, Alessandra
中科院分区：
文献类型：
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作者：
Brundu, Serena;Palma, Linda;Fraternale, Alessandra
将LP-BM 5鼠白血病病毒注射到小鼠体内会引起鼠AIDS，这是一种以免疫活性细胞的许多功能障碍为特征的疾病。为了确定该疾病是否以谷胱甘肽失衡为特征，在不同器官中定量测定还原型谷胱甘肽（GSH）和半胱氨酸。在淋巴器官（如脾脏和淋巴结）中发现了明显的氧化还原失衡，包括GSH和/或半胱氨酸耗竭。此外，在感染后5周，胰腺和大脑中的半胱氨酸和GSH水平分别显著降低。Th 1/Th 2细胞因子的表达表明，在所有研究时间，Th 2免疫应答均占主导地位。此外，对腹腔巨噬细胞活化状态的研究表明，诱导了交替活化的遗传标记物，即Fizz 1、Ym 1和精氨酸酶1的表达。相反，诱导型一氧化氮合酶的表达，经典的巨噬细胞活化的标志物，检测只有当Th 1细胞因子在高水平表达。体外研究表明，在感染的非常早期阶段，GSH耗竭和白细胞介素-12（IL-12）p40 mRNA的下调与用于感染巨噬细胞的LP-BM 5的剂量相关。用N-乙酰-L-半胱氨酰）-S-乙酰半胱胺（I-152）（一种N-乙酰半胱氨酸供应剂）治疗LP-BM 5感染的小鼠，恢复了器官中的GSH/半胱氨酸水平，降低了交替激活的巨噬细胞标志物的表达，并增加了γ干扰素的产生水平，同时降低了Th 2细胞因子（如IL-4和IL-5）的水平。因此，我们的研究结果确立了LP-BM 5感染中GSH缺乏与Th 1/Th 2失衡之间的联系，并表明I-152可用于恢复感染小鼠的GSH水平和平衡的Th 1/Th 2反应。重要信息首次报告了LP-BM 5感染中Th 2极化和氧化还原状态改变之间的联系。此外，它提供了LP-BM 5感染导致腹腔巨噬细胞巯基含量降低的证据，这可以影响IL-12的产生。通过GSH补充分子恢复GSH水平可以代表对抗这种逆转录病毒感染的新的治疗途径，因为它重建了Th 1/Th 2平衡。基于使用促GSH分子的免疫疗法将允许更有效地对抗LP-BM 5感染以及可能所有那些以GSH缺乏和Th 1/Th 2失衡为特征的病毒感染。
Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (I-152), an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL-4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice.IMPORTANCEThe first report of an association between Th2 polarization and alteration of the redox state in LP-BM5 infection is presented. Moreover, it provides evidence that LP-BM5 infection causes a decrease in the thiol content of peritoneal macrophages, which can influence IL-12 production. The restoration of GSH levels by GSH-replenishing molecules can represent a new therapeutic avenue to fight this retroviral infection, as it reestablishes the Th1/Th2 balance. Immunotherapy based on the use of pro-GSH molecules would permit LP-BM5 infection and probably all those viral infections characterized by GSH deficiency and a Th1/Th2 imbalance to be more effectively combated.