The role of sphingosine-1-phosphate transporter Spns2 in immune system function.
The role of sphingosine-1-phosphate transporter Spns2 in immune system function.
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DOI：
10.4049/jimmunol.1200282
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发表时间：
2012-07-01
期刊：
影响因子：
--
通讯作者：
Hancock RE
中科院分区：
文献类型：
--
作者：
Nijnik A;Clare S;Hale C;Chen J;Raisen C;Mottram L;Lucas M;Estabel J;Ryder E;Adissu H;Sanger Mouse Genetics Project;Adams NC;Ramirez-Solis R;White JK;Steel KP;Dougan G;Hancock RE
鞘氨醇-1-磷酸(S1P)是一种脂信使，参与调节胚胎发育、免疫系统功能等多种生理过程。然而，S1P跨细胞膜转运的机制仍然知之甚少，一些ATP结合盒家族成员和主要促进子超家族中的Spns2(Spns2)成员已知在细胞培养中介导S1P转运。Spns2还被证明在体内控制斑马鱼的S1P活性，并在斑马鱼的心血管发育中发挥关键作用。然而，Spns2在哺乳动物体内的作用及其在不同S1P依赖的生理过程中的作用尚未被研究。在这里，我们鉴定了携带Spns2tm1a(KOMP)WTSI等位基因(Spns2tm1a)的Spns2缺失小鼠品系。Spns2tm1a/tm1a动物是存活的，这表明Spns2的功能与其斑马鱼同源基因有所不同。然而，Spns2tm1a/tm1a小鼠的免疫表型与部分S1P缺乏和S1P依赖的淋巴细胞转运受损的表型非常相似，循环中的淋巴细胞枯竭，胸腺中成熟的单一阳性T细胞增加，而脾和骨髓中的成熟B细胞选择性减少。非造血细胞中的Spns2活性对正常淋巴细胞的发育和定位至关重要。总体而言，Spns2tm1a/tm1a导致对免疫的体液免疫反应受损。因此，这项工作证明了Spns2在哺乳动物免疫系统功能中的生理作用，而不是在心血管发育中。S1P信号网络的其他组成部分被作为免疫抑制治疗的药物靶点进行研究，但Spns2的选择性作用可能在这方面表现出优势。
Sphingosine-1-phosphate (S1P) is lipid messenger involved in the regulation of embryonic development, immune system functions, and many other physiological processes. However the mechanisms of S1P transport across cellular membranes remain poorly understood with several ATP-binding cassette family members and the spinster 2 (Spns2) member of the major facilitator superfamily known to mediate S1P transport in cell culture. Spns2 was also shown to control S1P activities in zebrafish in vivo and to play a critical role in zebrafish cardiovascular development. However the in vivo roles of Spns2 in mammals and its involvement in the different S1P-dependent physiological processes have not been investigated. Here we characterized Spns2-null mouse line carrying the Spns2tm1a(KOMP)Wtsi allele (Spns2tm1a). The Spns2tm1a/tm1a animals were viable, indicating a divergence in Spns2 function from its zebrafish orthologue. However the immunological phenotype of the Spns2tm1a/tm1a mice closely mimicked the phenotypes of partial S1P deficiency and impaired S1P-dependent lymphocyte trafficking, with a depletion of lymphocytes in circulation, an increase in mature single-positive T cells in the thymus, and a selective reduction in mature B cells in the spleen and bone marrow. Spns2 activity in the non-hematopoietic cells was critical for normal lymphocyte development and localization. Overall Spns2tm1a/tm1a resulted in impaired humoral immune responses to immunization. This work thus demonstrated a physiological role for Spns2 in mammalian immune system functions but not in cardiovascular development. Other components of the S1P signaling network are investigated as drug targets for immunosuppressive therapy, but the selective action of Spns2 may present an advantage in this regard.
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DOI：
10.1084/jem.20092210
发表时间：
2010-05-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Allende ML;Tuymetova G;Lee BG;Bonifacino E;Wu YP;Proia RL
通讯作者：
Proia RL
影响因子：
4.8
作者：
Haenel, Petra;Andreani, Paul;Graeler, Markus H.
通讯作者：
Graeler, Markus H.
影响因子：
4.8
作者：
Boujaoude, LC;Bradshaw-Wilder, C;Obeid, LM
通讯作者：
Obeid, LM
影响因子：
4.8
作者：
Allende, ML;Sasaki, T;Proia, RL
通讯作者：
Proia, RL
影响因子：
4.8
作者：
Hisano, Yu;Kobayashi, Naoki;Nishi, Tsuyoshi
通讯作者：
Nishi, Tsuyoshi