title: The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi.
abstract: Thrombosis promotes leukocyte infiltration into inflamed tissues, leading to organ injury in a broad range of diseases; however, the mechanisms by which thrombi guide leukocytes to sites of vascular injury remain ill-defined. Using mouse models of endothelial injury (traumatic or ischemia reperfusion), we demonstrate a distinct process of leukocyte recruitment, termed "directed intravascular migration," specifically mediated by platelet thrombi. Single adherent platelets and platelet aggregates stimulated leukocyte shape change at sites of endothelial injury; however, only thrombi were capable of inducing directed intravascular leukocyte migration. Leukocyte recruitment and migration induced by platelet thrombi occurred most prominently in veins but could also occur in arteries following ischemia-reperfusion injury. In vitro studies demonstrated a major role for platelet-derived NAP-2 (CXCL-7) and its CXCR1/2 receptor in regulating leukocyte polarization and motility. In vivo studies demonstrated the presence of an NAP-2 chemotactic gradient within the thrombus body. Pharmacologic blockade of CXCR1/2 as well as genetic deletion of NAP-2 markedly reduced leukocyte shape change and intrathrombus migration. These studies define a distinct process of leukocyte migration that is initiated by homotypic adhesive interactions between platelets, leading to the development of an NAP-2 chemotactic gradient within the thrombus body that guides leukocytes to sites of vascular injury.
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
authors.forename: Mehran
authors.initials: M
authors.lastname: Ghasemzadeh
authors.forename: Zane S
authors.initials: ZS
authors.lastname: Kaplan
authors.forename: Imala
authors.initials: I
authors.lastname: Alwis
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Ashworth
authors.forename: Erik
authors.initials: E
authors.lastname: Westein
authors.forename: Ehteramolsadat
authors.initials: E
authors.lastname: Hosseini
authors.forename: Hatem H
authors.initials: HH
authors.lastname: Salem
authors.forename: Robyn
authors.initials: R
authors.lastname: Slattery
authors.forename: Shaun R
authors.initials: SR
authors.lastname: McColl
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.forename: Zaverio M
authors.initials: ZM
authors.lastname: Ruggeri
authors.forename: Yuping
authors.initials: Y
authors.lastname: Yuan
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology; D019743:Chemokines, CXC / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007962:Leukocytes / Q000166:cytology* / Q000276:immunology; D008638:Mesenteric Arteries / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016602:Needlestick Injuries / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D023062:Receptors, Interleukin-8A / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology; D013927:Thrombosis / Q000276:immunology*
chemical_list: D019743:Chemokines, CXC; C446301:Cxcl7 protein, mouse; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D049452:Green Fluorescent Proteins
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