Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines
Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines
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DOI：
10.1002/hep.22443
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发表时间：
2008-10-01
期刊：
影响因子：
13.5
通讯作者：
Klugewitz, Katja
中科院分区：
文献类型：
--
作者：
Schrage, Arnhild;Wechsung, Katja;Klugewitz, Katja
通过肝内皮细胞的迁移是肝内T细胞动态平衡的先决条件，也是肝脏内炎症过程的关键调节因素。黏附分子和趋化因子及其受体在淋巴细胞和血管内皮细胞表面的不同表达模式调节着肝实质的外渗。在本研究中，我们研究了肝窦内皮细胞(LSEC)是否抑制或支持趋化因子驱动的移行，并对促炎症或抗炎的CD4(+)T细胞的移行产生不同的影响，揭示了肝脏免疫调节的机制。最后，这些结果阐明了LSEC调节趋化因子依赖的转运蛋白的分子机制。LSEC可显著增强CXC基序趋化因子配体12(CXCL12)和CXCL9的趋化效应，但CXCL16和CCL20对T辅助性T细胞1、辅助性T细胞2或白细胞介素10产生表型的幼稚和记忆性CD4+T细胞的趋化作用无显著差异。相反，脑和淋巴管内皮细胞以及体外分离的肺内皮细胞抑制了趋化因子驱动的转归。至于分子机制，通过阻断G(I)蛋白偶联信号和使用基因敲除小鼠来排除趋化因子诱导的LSEC的激活。在CXCL12预孵育到基底侧后，LSEC摄取CXCL12并促进移行，与存在可溶性趋化因子时一样有效。阻断LSec的跨胞作用可显著抑制这一效应，这表明趋化因子从内皮细胞的基底外侧摄取并呈现在管腔一侧，从而触发T细胞的迁移。结论：我们的研究结果显示了LSEC向循环淋巴细胞递送趋化因子的独特能力，并强调了内皮细胞在趋化因子体内效应中的重要性。LSEC提供的趋化因子可能为抑制淋巴细胞迁移和抑制肝脏炎症提供一个未来的治疗靶点。
Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells (LSEC) inhibit or support the chemokine-driven transmigration and differentially influence the transmigration of pro-inflammatory or anti-inflammatory CD4(+) T cells, indicating a mechanism of hepatic immunoregulation. Finally, the results shed light on the molecular mechanisms by which LSEC modulate chemokine-dependent transmigration. LSEC significantly enhanced the chemotactic effect of CXC-motif chemokine ligand 12 (CXCL12) and CXCL9, but not of CXCL16 or CCL20, on naive and memory CD4+ T cells of a T helper 1, T helper 2, or interieukin-10-producing phenotype. In contrast, brain and lymphatic endothelioma cells and ex vivo isolated lung endothelia inhibited chemokine-driven transmigration. As for the molecular mechanisms, chemokine-induced activation of LSEC was excluded by blockage of G(i)-protein-coupled signaling and the use of knockout mice. After preincubation of CXCL12 to the basal side, LSEC took up CXCL12 and enhanced transmigration as efficiently as in the presence of the soluble chemokine. Blockage of transcytosis in LSEC significantly inhibited this effect, and this suggested that chemokines taken up from the basolateral side and presented on the luminal side of endothelial cells trigger T cell transmigration. Conclusion: Our findings demonstrate a unique capacity of LSEC to present chemokines to circulating lymphocytes and highlight the importance of endothelial cells for the in vivo effects of chemokines. Chemokine presentation by LSEC could provide a future therapeutic target for inhibiting lymphocyte immigration and suppressing hepatic inflammation.