Vascular Cell Biology, Max Planck Institute of Molecular Biomedicine, Münster, Germany.
Elife. 2019 Aug 6;8:e47642. doi: 10.7554/eLife.47642.
Arrest of rapidly flowing neutrophils in venules relies on capturing through selectins and chemokine-induced integrin activation. Despite a long-established concept, we show here that gene inactivation of activating paired immunoglobulin-like receptor (PILR)-β1 nearly halved the efficiency of neutrophil arrest in venules of the mouse cremaster muscle. We found that this receptor binds to CD99, an interaction which relies on flow-induced shear forces and boosts chemokine-induced β-integrin-activation, leading to neutrophil attachment to endothelium. Upon arrest, binding of PILR-β1 to CD99 ceases, shifting the signaling balance towards inhibitory PILR-α. This enables integrin deactivation and supports cell migration. Thus, flow-driven shear forces guide sequential signaling of first activating PILR-β1 followed by inhibitory PILR-α to prompt neutrophil arrest and then transmigration. This doubles the efficiency of selectin-chemokine driven neutrophil arrest by PILR-β1 and then supports transition to migration by PILR-α.
中性粒细胞在小静脉中快速流动的捕获依赖于选择素和趋化因子诱导的整合素激活。尽管这是一个长期存在的概念，但我们在这里表明，激活配对免疫球蛋白样受体（PILR）-β1 的基因失活几乎将小鼠提睾肌小静脉中中性粒细胞捕获的效率降低了一半。我们发现该受体与 CD99 结合，这种相互作用依赖于流动诱导的剪切力，并增强趋化因子诱导的β整合素激活，导致中性粒细胞附着在内皮上。一旦被捕获，PILR-β1 与 CD99 的结合停止，信号转导平衡向抑制性 PILR-α 转移。这使得整合素失活并支持细胞迁移。因此，流动驱动的剪切力引导首先激活 PILR-β1 然后是抑制性 PILR-α 的顺序信号传导，以促使中性粒细胞捕获，然后迁移。这使得 PILR-β1 驱动的选择素-趋化因子驱动的中性粒细胞捕获效率提高了一倍，然后通过 PILR-α 支持向迁移的转变。
