The eicosanoid leukotriene B4 (LTB4) relays chemotactic signals to direct neutrophil migration to inflamed sites through its receptor BLT1. However, the mechanisms by which the LTB4–BLT1 axis relays chemotactic signals during intravascular neutrophil response to inflammation remain unclear. Here, we report that LTB4 produced by neutrophils acts as an autocrine/paracrine signal to direct the vascular recruitment, arrest, and extravasation of neutrophils in a sterile inflammation model in the mouse footpad. Using intravital subcellular microscopy, we reveal that LTB4 elicits sustained cell polarization and adhesion responses during neutrophil arrest in vivo. Specifically, LTB4 signaling coordinates the dynamic redistribution of non-muscle myosin IIA and β2-integrin, which facilitate neutrophil arrest and extravasation. Notably, we also found that neutrophils shed extracellular vesicles in the vascular lumen and that inhibition of extracellular vesicle release blocks LTB4-mediated autocrine/paracrine signaling required for neutrophil arrest and extravasation. Overall, we uncover a novel complementary mechanism by which LTB4 relays extravasation signals in neutrophils during early inflammation response.

中文翻译：

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LTB4-BLT1 轴在中性粒细胞外渗过程中调节肌动球蛋白和 β2-整合素动力学

类二十烷酸白三烯 B4 (LTB4) 传递趋化信号，通过其受体 BLT1 引导中性粒细胞迁移至发炎部位。然而，LTB4-BLT1 轴在血管内中性粒细胞对炎症反应期间传递趋化信号的机制仍不清楚。在此，我们报道中性粒细胞产生的 LTB4 作为自分泌/旁分泌信号，在小鼠足垫的无菌炎症模型中指导中性粒细胞的血管募集、停滞和外渗。使用活体亚细胞显微镜，我们揭示了 LTB4 在体内中性粒细胞停滞期间引发持续的细胞极化和粘附反应。具体来说，LTB4 信号传导协调非肌肉肌球蛋白 IIA 和 β2-整合素的动态重新分布，从而促进中性粒细胞停滞和外渗。值得注意的是，我们还发现中性粒细胞在血管腔中脱落细胞外囊泡，并且抑制细胞外囊泡释放会阻断中性粒细胞停滞和外渗所需的 LTB4 介导的自分泌/旁分泌信号传导。总体而言，我们发现了一种新的补充机制，LTB4 在早期炎症反应过程中通过该机制在中性粒细胞中传递外渗信号。