Platelet Extracellular Vesicles Drive Inflammasome–IL-1β–Dependent Lung Injury in Sickle Cell Disease
Year: 2019
Type: article
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.
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, American Heart Association, American Society of Hematology, University of Pittsburgh, Magee-Womens Research Institute, Hemophilia Center of Western Pennsylvania, National Institutes of Health, Pittsburgh Liver Research Center, University of Pittsburgh, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: Request for Zeiss 710 multiphoton 5Live Duoscan Microscope, G1232239498, G1315102726, G3531831431, Request for a Nikon A1R Multiphoton Microscope, Mechanism of platelet extracellular vesicle-mediated vaso-occlusion in Sickle Cell Disease, Heme-induced platelet mtROS drives TSP1 release to accelerate PH pathogenesis, Molecular Mechanism of Sickle Cell Hepatic Crisis, Mechanisms of platelet exosome-mediated acute chest syndrome in sickle cell disease, Pulmonary arteriole micro-embolism by platelet-neutrophil aggregates promotes sickle cell disease acute chest syndrome, Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome, Inflammasome activation in trauma-hemorrhagic shock, Cardiovascular Bioengineering Training Program, Mechanistic Elucidation and Targeted Therapy of Organ Injury and Inflammation following Trauma, Training in Translational Research in Pulmonary Vascular Biology
OpenAlex ID: W2972667849