The LTB(4)–BLT1 axis regulates actomyosin and β(2)-integrin dynamics during neutrophil extravasation

The eicosanoid leukotriene B(4) (LTB(4)) relays chemotactic signals to direct neutrophil migration to inflamed sites through its receptor BLT1. However, the mechanisms by which the LTB(4)–BLT1 axis relays chemotactic signals during intravascular neutrophil response to inflammation remain unclear. Here, we report that LTB(4) 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 LTB(4) elicits sustained cell polarization and adhesion responses during neutrophil arrest in vivo. Specifically, LTB(4) signaling coordinates the dynamic redistribution of non-muscle myosin IIA and β(2)-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 LTB(4)-mediated autocrine/paracrine signaling required for neutrophil arrest and extravasation. Overall, we uncover a novel complementary mechanism by which LTB(4) relays extravasation signals in neutrophils during early inflammation response.