Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation
Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation
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DOI：
10.1096/fj.10-177279
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发表时间：
2011-05-01
期刊：
影响因子：
4.8
通讯作者：
Verkman, A. S.
中科院分区：
文献类型：
--
作者：
Li, Lihua;Zhang, Hua;Verkman, A. S.
水通道蛋白-4 （AQP4）缺乏可减少髓鞘少突胶质细胞糖蛋白肽（MOG）主动免疫引起的实验性自身免疫性脑脊髓炎（EAE）小鼠的神经炎症。研究了AQP4缺乏保护作用的潜在机制，包括AQP4依赖性白细胞和小胶质细胞功能、免疫细胞进入中枢神经系统（CNS）、内在神经炎症和体液免疫反应。我们发现主动免疫EAE， aqp4敲除小鼠的神经炎症在过继转移EAE中大大减少。免疫细胞（包括活化的T淋巴细胞）中AQP4缺失。荧光标记、mog致敏的T淋巴细胞在野生型和aqp4敲除小鼠的中枢神经系统迁移相似。小胶质细胞不表达AQP4。EAE患者血清中无抗aqp4抗体。值得注意的是，与aqp4敲除小鼠相比，野生型小鼠脑内注射LPS产生了更大的神经炎症，aqp4敲除小鼠星形胶质细胞培养物中细胞因子（tnf - α和IL-6）分泌减少。腺病毒介导的AQP4或不相关的水通道蛋白AQP1的表达增加了星形胶质细胞和非星形胶质细胞培养物中细胞因子的分泌，支持水通道蛋白的水渗透性参与细胞因子的分泌。我们的数据表明AQP4具有内在的促炎作用，涉及AQP4依赖性星形胶质细胞肿胀和细胞因子释放。AQP4水转运的减少可能对神经炎性中枢神经系统疾病具有保护作用。-李丽丽，张洪，Varrin-Doyer， M., Zamvil, s.s S, Verkman， A.。水通道蛋白-4在自身免疫性神经炎症中的促炎作用。中华医学杂志，25,(2011):1556-1566。www.fasebj.org
Aquaporin-4 (AQP4) deficiency in mice reduces neuroinflammation in experimental autoimmune encephalomyelitis (EAE) produced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOG). Potential mechanisms for the protective effect of AQP4 deficiency were investigated, including AQP4-dependent leukocyte and microglia cell function, immune cell entry in the central nervous system (CNS), intrinsic neuroinflammation, and humoral immune response. As we found with active-immunization EAE, neuroinflammation was greatly reduced in AQP4-knockout mice in adoptive-transfer EAE. AQP4 was absent in immune cells, including activated T lymphocytes. The CNS migration of fluorescently labeled, MOG-sensitized T lymphocytes was comparable in wild-type and AQP4-knockout mice. Microglia did not express AQP4. Serum anti-AQP4 antibodies were absent in EAE. Remarkably, intracerebral injection of LPS produced much greater neuroinflammation in wild-type than in AQP4-knockout mice, and cytokine (TNF-alpha and IL-6) secretion was reduced in astrocyte cultures from AQP4-knockout mice. Adenovirus-mediated expression of AQP4, or of an unrelated aquaporin, AQP1, increased cytokine secretion in astrocyte and nonastrocyte cell cultures, supporting the involvement of aquaporin water permeability in cytokine secretion. Our data suggest an intrinsic proinflammatory role of AQP4 involving AQP4-dependent astrocyte swelling and cytokine release. Reduction in AQP4 water transport may be protective in neuroinflammatory CNS diseases.-Li, L., Zhang, H., Varrin-Doyer, M., Zamvil, S. S., Verkman, A. S. Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation. FASEB J. 25, 1556-1566 (2011). www.fasebj.org