Rationale: Intraerythrocytic polymerization of Hb S promotes hemolysis and vasoocclusive events in the microvasculature of patients with sickle cell disease (SCD). Although platelet–neutrophil aggregate–dependent vasoocclusion is known to occur in the lung and contribute to acute chest syndrome, the etiological mechanisms that trigger acute chest syndrome are largely unknown.

Objectives: To identify the innate immune mechanism that promotes platelet–neutrophil aggregate–dependent lung vasoocclusion and injury in SCD.

Methods: In vivo imaging of the lung in transgenic humanized SCD mice and in vitro imaging of SCD patient blood flowing through a microfluidic system was performed. SCD mice were systemically challenged with nanogram quantities of LPS to trigger lung vasoocclusion.

Measurements and Main Results: Platelet–inflammasome activation led to generation of IL-1β and caspase-1–carrying platelet extracellular vesicles (EVs) that bind to neutrophils and promote platelet–neutrophil aggregation in lung arterioles of SCD mice in vivo and SCD human blood in microfluidics in vitro. The inflammasome activation, platelet EV generation, and platelet–neutrophil aggregation were enhanced by the presence of LPS at a nanogram dose in SCD but not control human blood. Inhibition of the inflammasome effector caspase-1 or IL-1β pathway attenuated platelet EV generation, prevented platelet–neutrophil aggregation, and restored microvascular blood flow in lung arterioles of SCD mice in vivo and SCD human blood in microfluidics in vitro.

Conclusions: These results are the first to identify that platelet–inflammasome–dependent shedding of IL-1β and caspase-1–carrying platelet EVs promote lung vasoocclusion in SCD. The current findings also highlight the therapeutic potential of targeting the platelet–inflammasome–dependent innate immune pathway to prevent acute chest syndrome.