title: P-selectin promotes neutrophil extracellular trap formation in mice.
abstract: Neutrophil extracellular traps (NETs) can be released in the vasculature. In addition to trapping microbes, they promote inflammatory and thrombotic diseases. Considering that P-selectin induces prothrombotic and proinflammatory signaling, we studied the role of this selectin in NET formation. NET formation (NETosis) was induced by thrombin-activated platelets rosetting with neutrophils and was inhibited by anti-P-selectin aptamer or anti-P-selectin glycoprotein ligand-1 (PSGL-1) inhibitory antibody but was not induced by platelets from P-selectin(-/-) mice. Moreover, NETosis was also promoted by P-selectin-immunoglobulin fusion protein but not by control immunoglobulin. We isolated neutrophils from mice engineered to overproduce soluble P-selectin (P-selectin(ΔCT/ΔCT) mice). Although the levels of circulating DNA and nucleosomes (indicative of spontaneous NETosis) were normal in these mice, basal neutrophil histone citrullination and presence of P-selectin on circulating neutrophils were elevated. NET formation after stimulation with platelet activating factor, ionomycin, or phorbol 12-myristate 13-acetate was significantly enhanced, indicating that the P-selectin(ΔCT/ΔCT) neutrophils were primed for NETosis. In summary, P-selectin, cellular or soluble, through binding to PSGL-1, promotes NETosis, suggesting that this pathway is a potential therapeutic target for NET-related diseases.
authors.affiliation: Laboratory of Experimental Thrombosis, Institute of Experimental Medicine, National Scientific and Technical Research Council, National Academy of Medicine, Buenos Aires, Argentina; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA;
authors.forename: Julia
authors.initials: J
authors.lastname: Etulain
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Pediatrics, and Immunology Graduate Program, Division of Medical Sciences, Harvard Medical School, Boston, MA; and.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Martinod
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Pediatrics, and.
authors.forename: Siu Ling
authors.initials: SL
authors.lastname: Wong
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA;
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cifuni
authors.affiliation: Laboratory of Experimental Thrombosis, Institute of Experimental Medicine, National Scientific and Technical Research Council, National Academy of Medicine, Buenos Aires, Argentina;
authors.forename: Mirta
authors.initials: M
authors.lastname: Schattner
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Pediatrics, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D065206:Extracellular Traps / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015539:Platelet Activation / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013927:Thrombosis / Q000235:genetics* / Q000473:pathology; D014657:Vasculitis / Q000235:genetics* / Q000473:pathology
chemical_list: D019007:P-Selectin; D011993:Recombinant Fusion Proteins