Spinster 2, a sphingosine-1-phosphate transporter, plays a critical role in inflammatory and autoimmune diseases
Spinster 2, a sphingosine-1-phosphate transporter, plays a critical role in inflammatory and autoimmune diseases
复制标题
DOI：
10.1096/fj.15-274936
复制
发表时间：
2015-12-01
期刊：
影响因子：
4.8
通讯作者：
Spiegel, Sarah
中科院分区：
文献类型：
--
作者：
Donoviel, Michael S.;Hait, Nitai C.;Spiegel, Sarah
1-磷酸鞘氨醇 (S1P) 是一种多效性生物活性鞘脂代谢物，可调节对免疫反应重要的许多过程。 S1P 在细胞内产生，必须被转运出细胞才能通过以自分泌或旁分泌方式激活 5 个特定细胞表面 GPCR 来发挥其作用。 Spinster 2 (Spns2) 将 S1P 转运出细胞，其在小鼠体内的缺失会降低 S1P 的循环水平，改变免疫细胞运输，并诱导淋巴细胞减少。在这里，我们研究了 Spns2 缺失对适应性免疫反应和自身免疫疾病模型的影响。 Spns2(-/-)小鼠的气道炎症和超敏反应以及迟发型接触超敏反应均减弱。同样，Spns2 缺失可减少葡聚糖硫酸钠和恶唑酮诱导的结肠炎。有趣的是，Spns2(-/-) 小鼠免受实验性自身免疫性脑病（一种自身免疫性疾病多发性硬化症的模型）的发展。 Spns2 的缺失也极大地减轻了胶原诱导的关节炎的疾病发展。这些结果表明 Spns2 介导的 S1P 转运在适应性免疫相关疾病的发生和发展中发挥着广泛作用。
Sphingosine 1-phosphate (S1P) is a pleiotropic bioactive sphingolipid metabolite that regulates numerous processes important for immune responses. S1P is made within cells and must be transported out of cells to exert its effects through activation of 5 specific cell surface GPCRs in an autocrine or paracrine fashion. Spinster 2 (Spns2) transports S1P out of cells, and its deletion in mice reduces circulating levels of S1P, alters immune cell trafficking, and induces lymphopenia. Here we examined the effects of Spns2 deletion on adaptive immune responses and in autoimmune disease models. Airway inflammation and hypersensitivity as well as delayed-type contact hypersensitivity were attenuated in Spns2(-/-) mice. Similarly, Spns2 deletion reduced dextran sodium sulfate- and oxazolone-induced colitis. Intriguingly, Spns2(-/-) mice were protected from the development of experimental autoimmune encephalopathy, a model of the autoimmune disease multiple sclerosis. Deletion of Spns2 also strongly alleviated disease development in collagen-induced arthritis. These results point to a broad role for Spns2-mediated S1P transport in the initiation and development of adaptive immune related disorders.