LAUSR

Acute lung injury, referred to as the acute chest syndrome, is a major cause of morbidity and mortality in patients with sickle cell disease (SCD), which often occurs in the setting of a vaso-occlusive painful crisis. P-selectin antibody therapy reduces hospitalization of SCD patients by almost 50%, suggesting that an unknown P-selectin-independent mechanism promotes remaining vaso-occlusive events. In SCD patients, intra-erythrocytic polymerization of mutant hemoglobin promotes ischemia-reperfusion injury and hemolysis, which leads to the development of sterile inflammation. Using intravital microscopy in transgenic, humanized SCD mice and in vitro studies with blood from SCD patients, we reveal for the first time that the sterile inflammatory milieu in SCD promotes caspase-4/11-dependent activation of neutrophil-Gasdermin-D (GSDMD), which triggers P-selectin-independent shedding of neutrophil extracellular traps (NETs) in the liver. Remarkably, these NETs travel intravascularly from liver to lung, where they promote neutrophil-platelet aggregation and the development of acute lung injury. This study introduces a novel paradigm that liver to lung embolic translocation of NETs promotes pulmonary vascular vaso-occlusion, and identifies a new GSDMD-mediated, P-selectin-independent mechanism of lung injury in SCD.