HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation.
HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation.
复制标题
DOI：
10.1038/nature14462
复制
发表时间：
2015-07-16
期刊：
影响因子：
64.8
通讯作者：
Hla T
中科院分区：
文献类型：
--
作者：
Blaho VA;Galvani S;Engelbrecht E;Liu C;Swendeman SL;Kono M;Proia RL;Steinman L;Han MH;Hla T
脂质介质以多种方式影响免疫。例如，循环鞘氨醇1-磷酸（S1P）是淋巴细胞分泌的关键调节因子。虽然大部分血浆S1P与高密度脂蛋白（HDL）颗粒中的载脂蛋白M （ApoM）结合，但ApoM-S1P复合物的免疫功能尚不清楚。在这里，我们发现ApoM-S1P对于淋巴细胞运输是必不可少的，但通过激活骨髓（BM）淋巴细胞祖细胞上的S1P1受体来抑制淋巴细胞生成。缺乏ApoM （ApoM−/−）的小鼠BM中Lin - Sca1+cKit+造血祖细胞（LSK）和共同淋巴样祖细胞（CLP）的增殖增加。体内S1P1的药理激活或基因过表达抑制LSK和CLP的增殖。ApoM与BM CLPs稳定相关，在体内显示活跃的S1P1信号。此外，ApoM+HDL，而不是白蛋白结合的S1P，在体外抑制淋巴生成。在免疫刺激下，Apom - / -小鼠出现了更严重的实验性自身免疫性脑脊髓炎，其特征是中枢神经系统（CNS）淋巴细胞增加和血脑屏障破坏。因此，ApoM-S1P-S1P1信号轴抑制淋巴细胞室和随后的适应性免疫反应。特定的S1P伴侣赋予的独特生物学功能可以被用于新的治疗机会。
Lipid mediators influence immunity in myriad ways. For example, circulating sphingosine 1-phosphate (S1P) is a key regulator of lymphocyte egress. Although the majority of plasma S1P is bound to apolipoprotein M (ApoM) in the high-density lipoprotein (HDL) particle, immunological functions of the ApoM-S1P complex are unknown. Here, we show that ApoM-S1P is dispensable for lymphocyte trafficking yet restrains lymphopoiesis by activating the S1P1 receptor on bone marrow (BM) lymphocyte progenitors. Mice that lacked ApoM (Apom−/−) had increased proliferation of Lin−Sca1+cKit+ hematopoietic progenitor cells (LSK) and common lymphoid progenitors (CLP) in BM. Pharmacologic activation or genetic overexpression of S1P1 suppressed LSK and CLP proliferation in vivo. ApoM was stably associated with BM CLPs, which showed active S1P1 signaling in vivo. Moreover, ApoM+HDL, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom−/− mice developed more severe experimental autoimmune encephalomyelitis, characterized by increased lymphocytes in the central nervous system (CNS) and breakdown of the blood-brain barrier. Thus, the ApoM-S1P-S1P1 signaling axis restrains the lymphocyte compartment and subsequently, adaptive immune responses. Unique biological functions imparted by specific S1P chaperones could be exploited for novel therapeutic opportunities.