Platelet Extracellular Vesicles Drive Inflammasome-IL-1β-Dependent Lung Injury in Sickle Cell Disease

Am J Respir Crit Care Med. 2020 Jan 1;201(1):33-46. doi: 10.1164/rccm.201807-1370OC.

Abstract

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.

Keywords: acute chest syndrome; neutrophil–platelet aggregates; vasoocclusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Chest Syndrome / etiology
  • Acute Chest Syndrome / physiopathology
  • Anemia, Sickle Cell / complications*
  • Anemia, Sickle Cell / immunology*
  • Anemia, Sickle Cell / physiopathology
  • Animals
  • Extracellular Vesicles / immunology*
  • Humans
  • Inflammasomes / immunology*
  • Lung Injury / etiology*
  • Lung Injury / physiopathology*
  • Mice
  • Mice, Transgenic
  • Models, Animal
  • Neutrophils / immunology
  • Platelet Aggregation / immunology*

Substances

  • Inflammasomes