Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo
Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo
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DOI：
10.1038/nchembio804
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发表时间：
2006-08-01
影响因子：
14.8
通讯作者：
Rosen, Hugh
中科院分区：
文献类型：
--
作者：
Sanna, M. Germana;Wang, Sheng-Kai;Rosen, Hugh
1-磷酸鞘氨醇（S1 P，1）通过激活高亲和力S1 P1受体调节血管屏障和淋巴发育，以及淋巴细胞从淋巴器官的排出。我们使用可逆化学探针（i）获得对S1 P系统组织的机械见解，这些组织通过遗传操作无法获得，（ii）研究其治疗调节的潜力。血管（而非气道）给药体内活性手性S1 P1受体拮抗剂的优选R对映体诱导小鼠皮肤和肺毛细血管完整性丧失。相反，拮抗剂不影响组成性血液淋巴细胞的数量。相反，淋巴细胞运输和表型的改变需要超生理升高的S1 P1音，并逆转拮抗剂。淋巴结的体内双光子成像证实了专性激动作用的要求，并且数据与门控淋巴细胞排出的基质屏障机制的存在一致。因此，化学调节揭示了组织之间S1 P-S1 P（1）“设定点”的差异，并突出了治疗干预的机制优势（淋巴细胞隔离）和风险（肺水肿）。
Sphingosine 1-phosphate (S1P, 1) regulates vascular barrier and lymphoid development, as well as lymphocyte egress from lymphoid organs, by activating high-affinity S1P1 receptors. We used reversible chemical probes (i) to gain mechanistic insights into S1P systems organization not accessible through genetic manipulations and (ii) to investigate their potential for therapeutic modulation. Vascular (but not airway) administration of the preferred R enantiomer of an in vivo-active chiral S1P1 receptor antagonist induced loss of capillary integrity in mouse skin and lung. In contrast, the antagonist did not affect the number of constitutive blood lymphocytes. Instead, alteration of lymphocyte trafficking and phenotype required supraphysiological elevation of S1P1 tone and was reversed by the antagonist. In vivo two-photon imaging of lymph nodes confirmed requirements for obligate agonism, and the data were consistent with the presence of a stromal barrier mechanism for gating lymphocyte egress. Thus, chemical modulation reveals differences in S1P-S1P(1) 'set points' among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention.