Aquaporin 4 inhibition alters chemokine receptor expression and T cell trafficking
Aquaporin 4 inhibition alters chemokine receptor expression and T cell trafficking
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DOI：
10.1038/s41598-019-43884-2
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发表时间：
2019-05-15
影响因子：
4.6
通讯作者：
Valujskikh, Anna
中科院分区：
文献类型：
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作者：
Nicosia, Michael;Miyairi, Satoshi;Valujskikh, Anna
水通道蛋白(AQP)是一种调节多种生物过程的水通道。然而，它们在免疫系统中的作用却知之甚少。我们最近报道，AQP4是由幼稚和记忆T细胞表达的，用小分子抑制剂阻断AQP4至少部分地通过减少T细胞的活化、增殖和运输来延长小鼠同种异体心脏移植物的存活。这项研究的目的是确定在缺乏抗原刺激的情况下，AQP4的功能如何影响T细胞。在没有全身性T细胞耗竭的情况下，抑制AQP4可以暂时减少未移植小鼠循环中的CD4+和CD8+T细胞的数量。过继转移研究证实了AQP4抑制T细胞的内在效应。AQP4阻断可改变T细胞趋化因子受体S1PR1和CCR7及其主要调控因子KLF-2的基因和蛋白表达，降低对S1P和CCL21的趋化能力。与体外数据一致，体内AQP4抑制减少了淋巴结中的T淋巴细胞数量，同时也积聚在肝脏中。我们的发现表明，阻断AQP4可逆地改变T淋巴细胞的运输模式。这些信息可用于治疗移植受者或自身免疫性疾病患者的不良免疫反应。
Aquaporins (AQPs) are water channels that mediate a variety of biological processes. However, their role in the immune system is poorly understood. We recently reported that AQP4 is expressed by naive and memory T cells and that AQP4 blockade with a small molecule inhibitor prolongs murine heart allograft survival at least partially through diminishing T cell activation, proliferation and trafficking. The goal of this study was to determine how AQP4 function impacts T cells in the absence of antigen stimulation. AQP4 inhibition transiently reduced the number of circulating CD4+ and CD8+ T cells in naive non-transplanted mice in the absence of systemic T cell depletion. Adoptive transfer studies demonstrated T cell intrinsic effect of AQP4 inhibition. AQP4 blockade altered T cell gene and protein expression of chemokine receptors S1PR1 and CCR7, and their master regulator KLF-2, and reduced chemotaxis toward S1P and CCL21. Consistent with the in vitro data, in vivo AQP4 inhibition reduced T lymphocyte numbers in the lymph nodes with simultaneous accumulation in the liver. Our findings indicate that blocking AQP4 reversibly alters T lymphocyte trafficking pattern. This information can be explored for the treatment of undesirable immune responses in transplant recipients or in patients with autoimmune diseases.