Migrational guidance of neutrophils is mechanotransduced via high-affinity LFA-1 and calcium flux.
Migrational guidance of neutrophils is mechanotransduced via high-affinity LFA-1 and calcium flux.
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中性粒细胞的迁移引导是通过高亲和力LFA-1和钙通量来机械转化的。
DOI：
10.4049/jimmunol.1004197
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发表时间：
2011-07-01
期刊：
影响因子：
--
通讯作者：
Simon SI
中科院分区：
文献类型：
--
作者：
Dixit N;Yamayoshi I;Nazarian A;Simon SI
急性炎症触发中性粒细胞的先天免疫反应，其有效地从血流中运输，以大量聚集在组织感染或创伤部位。该过程中的守门人是β2整联蛋白的活化，其与内皮表面上的ICAM-1形成键簇。这些键簇具有双重功能，即在血流的剪切力下为锚中性粒细胞提供粘附强度，以及为细胞极化和随后在发炎内皮上的迁移提供方向性引导。我们假设，通过高亲和力LFA-1传递的剪切力促进了与钙释放激活通道Orai 1在定向局部细胞骨架激活和定向迁移中的合作。通过使用血管模拟微流体通道，我们观察到中性粒细胞在ICAM-1或变构抗体的底物上的停滞，所述变构抗体稳定LFA-1的高或低亲和力构象。通过低亲和力LFA-1捕获的中性粒细胞没有表现出细胞内钙流，F-肌动蛋白聚合，细胞极化，或剪切流下的定向迁移。相比之下，高亲和力LFA-1提供的方向沿着尾足伪足轴，需要通过Orai 1钙流量。我们证明了血流的剪切力如何在高亲和力LFA-1的焦点部位产生不同的由外向内的信号，这些信号为中性粒细胞迁移提供了接触介导的指导。
Acute inflammation triggers the innate immune response of neutrophils that efficiently traffic from the bloodstream to concentrate at high numbers at the site of tissue infection or wounding. A gatekeeper in this process is activation of β2 integrins, which form bond clusters with ICAM-1 on the endothelial surface. These bond clusters serve dual functions of providing adhesive strength to anchor neutrophils under the shear forces of blood flow and directional guidance for cell polarization and subsequent transmigration on inflamed endothelium. We hypothesized that shear forces transmitted through high-affinity LFA-1 facilitates the cooperation with the calcium release-activated channel Orai1 in directing localized cytoskeletal activation and directed migration. By using vascular mimetic microfluidic channels, we observed neutrophil arrest on a substrate of either ICAM-1 or allosteric Abs that stabilize a high- or low-affinity conformation of LFA-1. Neutrophils captured via low-affinity LFA-1 did not exhibit intracellular calcium flux, F-actin polymerization, cell polarization, or directional migration under shear flow. In contrast, high-affinity LFA-1 provided orientation along a uropod–pseudopod axis that required calcium flux through Orai1. We demonstrate how the shear stress of blood flow can transduce distinct outside–in signals at focal sites of high-affinity LFA-1 that provide contact-mediated guidance for neutrophil emigration.
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