E-selectin extends from the plasma membrane of inflamed endothelium and serves to capture leukocytes from flowing blood via long-lived catch-bonds that support slow leukocyte rolling under shear stress. Its ligands are glycosylated with the tetrasaccharide sialyl Lewis^x (sLe^x), which contributes to bond affinity and specificity. E-selectin-mediated rolling transmits signals into neutrophils that trigger activation of high-affinity β₂-integrins necessary for transition to shear-resistant adhesion and transendothelial migration. Rivipansel is a glycomimetic drug that inhibits E-selectin-mediated vaso-occlusion induced by integrin-dependent sickle–red blood cell–leukocyte adhesion. How Rivipansel antagonizes ligand recognition by E-selectin and blocks outside-in signaling of integrin-mediated neutrophil arrest while maintaining rolling immune-surveillance is unknown. Here, we demonstrate that sLe^x expressed on human L-selectin is preferentially bound by E-selectin and, on ligation, initiates secretion of MRP8/14 that binds TLR4 to elicit the extension of β₂-integrin to an intermediate affinity state. Neutrophil rolling over E-selectin at precise shear stress transmits tension and catch-bond formation with L-selectin via sLe^x, resulting in focal clusters that deliver a distinct signal to upshift β₂-integrins to a high-affinity state. Rivipansel effectively blocked formation of selectin catch-bonds, revealing a novel mechanotransduction circuit that rapidly converts extended β₂-integrins to high-affinity shear-resistant bond clusters with intracellular adhesion molecule 1 on inflamed endothelium.

E-选择蛋白从发炎的内皮细胞的质膜延伸，并通过长寿命的捕获键从流动的血液中捕获白细胞，该捕获键支持在剪切应力下缓慢的白细胞滚动。它的配体被四糖唾液酸路易斯^x（sLe ^x）糖基化，这有助于键的亲和力和特异性。E-selectin介导的轧制发送信号转换成嗜中性粒细胞的是触发激活的高亲和力β ₂-整合素是过渡到抗剪切粘附和跨内皮迁移所必需的。Rivipansel是一种拟糖药物，可抑制由整合素依赖性镰刀-红细胞-白细胞粘附引起的E-选择蛋白介导的血管闭塞。Rivipansel如何通过E-选择素拮抗配体识别并阻断整合素介导的嗜中性白细胞停滞的外向内信号转导，同时保持滚动免疫监测。在这里，我们证明了SLE ^X表示对人类L-选择优先被E-选择约束和上结扎，MRP8 / 14的发起分泌结合TLR4引起的β延伸₂-整联蛋白到中间亲和力状态。嗜中性粒细胞滚过E-选择以精确的剪切应力发送张力和catch键形成与L-选择经由SLE ^X，导致焦集群升挡β，可提供不同的信号_2个-integrins到的高亲和力状态。Rivipansel有效地阻止形成的选择追键，揭示一种新颖的机械传导电路，其迅速转换延长β _2个-integrins与发炎的内皮细胞内粘附分子1的高亲和性抗剪切键簇。