title: Directed transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response.
abstract: The innate immune response to bacterial infections requires the interaction of neutrophils and platelets. Here, we show that a multistep reciprocal crosstalk exists between these two cell types, ultimately facilitating neutrophil influx into the lung to eliminate infections. Activated platelets adhere to intravascular neutrophils through P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1)-mediated binding, a primary interaction that allows platelets glycoprotein Ibα (GPIbα)-induced generation of neutrophil-derived extracellular vesicles (EV). EV production is directed by exocytosis and allows shuttling of arachidonic acid into platelets. EVs are then specifically internalized into platelets in a Mac1-dependent fashion, and relocated into intracellular compartments enriched in cyclooxygenase1 (Cox1), an enzyme processing arachidonic acid to synthesize thromboxane A2(TxA2). Finally, platelet-derived-TxA2elicits a full neutrophil response by inducing the endothelial expression of ICAM-1, intravascular crawling, and extravasation. We conclude that critical substrate-enzyme pairs are compartmentalized in neutrophils and platelets during steady state limiting non-specific inflammation, but bacterial infection triggers regulated EV shuttling resulting in robust inflammation and pathogen clearance.
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kühne
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Skupski
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Hugo
authors.initials: H
authors.lastname: Van Aken
authors.affiliation: Department of Medicine, University of California, San Francisco, California 94143, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Looney
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80336 Munich, Germany.|Area of Cell and Developmental Biology, CNIC, 28029 Madrid, Spain.
authors.forename: Andres
authors.identifier: 0000-0001-5513-555X
authors.initials: A
authors.lastname: Hidalgo
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology* / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000276:immunology* / Q000378:metabolism; D007109:Immunity / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D019007:P-Selectin / Q000276:immunology / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000276:immunology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013928:Thromboxane A2 / Q000276:immunology / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D019038:Platelet Glycoprotein GPIb-IX Complex; D013928:Thromboxane A2; D051545:Cyclooxygenase 1