Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation.
Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation.
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DOI：
10.1038/ncomms8965
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发表时间：
2015-08-05
影响因子：
16.6
通讯作者：
Isakson BE
中科院分区：
文献类型：
--
作者：
Lohman AW;Leskov IL;Butcher JT;Johnstone SR;Stokes TA;Begandt D;DeLalio LJ;Best AK;Penuela S;Leitinger N;Ravichandran KS;Stokes KY;Isakson BE
炎症细胞向组织损伤和/或感染的局部部位的募集受影响毛细血管后小静脉中的血管内皮细胞（EC）与循环白细胞之间的细胞-细胞相互作用的过多信号传导过程控制。最近，ATP敏感的P2 Y嘌呤能受体已成为血管炎症中EC激活的下游调节因子。然而，在这种反应中调节细胞ATP释放的机制仍然难以捉摸。在这里，我们报告了ATP释放通道Pannexin 1（Panx 1）在TNF-α激活EC的下游开放。该过程涉及1型TNF受体的激活、Src家族激酶（SFK）的募集和Panx 1的SFK依赖性磷酸化。使用诱导型，EC特异性Panx 1基因敲除小鼠系，我们报告了先前未确定的作用Panx 1通道促进白细胞粘附和移民通过静脉壁在急性全身性炎症，将Panx 1通道的细胞因子串扰的中心与内皮细胞中的嘌呤能信号。 炎症引起的内皮细胞活化需要细胞外ATP释放。在这里，作者表明TNF-α通过内皮细胞中的Pannexin 1通道诱导Src家族激酶依赖性ATP释放，并且Pannexin 1是白细胞粘附和迁移到炎症组织中所必需的。
Inflammatory cell recruitment to local sites of tissue injury and/or infection is controlled by a plethora of signalling processes influencing cell-to-cell interactions between the vascular endothelial cells (ECs) in post-capillary venules and circulating leukocytes. Recently, ATP-sensitive P2Y purinergic receptors have emerged as downstream regulators of EC activation in vascular inflammation. However, the mechanism(s) regulating cellular ATP release in this response remains elusive. Here we report that the ATP-release channel Pannexin1 (Panx1) opens downstream of EC activation by TNF-α. This process involves activation of type-1 TNF receptors, recruitment of Src family kinases (SFK) and SFK-dependent phosphorylation of Panx1. Using an inducible, EC-specific Panx1 knockout mouse line, we report a previously unidentified role for Panx1 channels in promoting leukocyte adhesion and emigration through the venous wall during acute systemic inflammation, placing Panx1 channels at the centre of cytokine crosstalk with purinergic signalling in the endothelium. Endothelial cell activation by inflammation requires extracellular ATP release. Here the authors show that TNF-α induces Src-family kinase-dependent ATP release by Pannexin1 channels in endothelial cells, and that Pannexin1 is required for leukocyte adhesion and emigration into the inflamed tissue.