HETEROTYPIC INTERACTIONS ENABLED BY POLARIZED NEUTROPHIL MICRODOMAINS MEDIATE THROMBO-INFLAMMATORY INJURY

Selectins and their ligands mediate leukocyte rolling allowing interactions with chemokines that lead to integrin activation and arrest. Here, we demonstrate that E-selectin is critical to induce a secondary wave of activating signals transduced specifically by E-selectin ligand-1, that induces polarized, activated αMβ2 integrin clusters at the leading edge of crawling neutrophils, allowing the capture of circulating erythrocytes or platelets. In a humanized model of sickle cell disease (SCD), the capture of erythrocytes by αMβ2 microdomains leads to acute lethal vascular occlusions. In a model of transfusion-related acute lung injury, polarized neutrophils capture circulating platelets, resulting in the generation of oxidative species that produces vascular damage and lung injury. Inactivation of E-selectin or αMβ2 prevented tissue injury in both inflammatory models, suggesting broad implications of this paradigm in thrombo-inflammatory diseases. These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation.