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摘要 : “1- 磷酸鞘氨醇” (S1P)是集中在血液和淋巴中的一种脂质介质,是调控各种不同生理功能的一种信号。它通过“G-蛋白耦合受体”来发挥作用,调控免疫细胞贩运。

 “1- 磷酸鞘氨醇” (S1P)是集中在血液和淋巴中的一种脂质介质,是调控各种不同生理功能的一种信号。它通过“G-蛋白耦合受体”来发挥作用,调控免疫细胞贩运。这项研究显示,结合到其伴侣分子 “阿普脂蛋白M”(ApoM)上的S1P,通过激活小鼠的骨髓淋巴细胞的祖细胞上的S1P1受体来抑制新的淋巴细胞的生成,从而也抑制自适应免疫反应。然而,ApoM–S1P并不是淋巴细胞贩运所需的,后者是由血浆S1P执行的一个功能,而血浆S1P则是最近被批准用于治疗多发性硬化的免疫调控药物“芬戈莫德”(fingolimod)的一个作用目标。


HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation


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, the 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 lymphocyte progenitors. Mice that lacked ApoM (Apom−/−) had increased proliferation of Lin− Sca-1+ cKit+ haematopoietic progenitor cells (LSKs) and common lymphoid progenitors (CLPs) in bone marrow. Pharmacological activation or genetic overexpression of S1P1 suppressed LSK and CLP cell proliferation in vivo. ApoM was stably associated with bone marrow CLPs, which showed active S1P1 signalling in vivo4. Moreover, ApoM-bound S1P, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom−/− mice developed more severe experimental autoimmune encephalomyelitis5, characterized by increased lymphocytes in the central nervous system and breakdown of the blood–brain barrier. Thus, the ApoM–S1P–S1P1signalling 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.

来源: Nature 浏览次数:0


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