title: Leukotriene B4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo.
abstract: Breaching endothelial cells (ECs) is a decisive step in the migration of leukocytes from the vascular lumen to the extravascular tissue, but fundamental aspects of this response remain largely unknown. We have previously shown that neutrophils can exhibit abluminal-to-luminal migration through EC junctions within mouse cremasteric venules and that this response is elicited following reduced expression and/or functionality of the EC junctional adhesion molecule-C (JAM-C). Here we demonstrate that the lipid chemoattractant leukotriene B4 (LTB4) was efficacious at causing loss of venular JAM-C and promoting neutrophil reverse transendothelial cell migration (rTEM) in vivo. Local proteolytic cleavage of EC JAM-C by neutrophil elastase (NE) drove this cascade of events as supported by presentation of NE to JAM-C via the neutrophil adhesion molecule Mac-1. The results identify local LTB4-NE axis as a promoter of neutrophil rTEM and provide evidence that this pathway can propagate a local sterile inflammatory response to become systemic.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Bartomeu
authors.initials: B
authors.lastname: Colom
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Bodkin
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Beyrau
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Abigail
authors.initials: A
authors.lastname: Woodfin
authors.affiliation: Centre Médical Universitaire, Rue Michel-Servet 1, Geneva CH-1211, Switzerland.
authors.forename: Christiane
authors.initials: C
authors.lastname: Ody
authors.affiliation: Centre for Trauma Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Mile End Road, London E1 4NS, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Rourke
authors.affiliation: Department of Clinical Pathobiochemistry, University of Dresden, Fetscherstrasse 74, Dresden 01307, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Centre for Trauma Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Mile End Road, London E1 4NS, UK.
authors.forename: Karim
authors.initials: K
authors.lastname: Brohi
authors.affiliation: Centre Médical Universitaire, Rue Michel-Servet 1, Geneva CH-1211, Switzerland.
authors.forename: Beat A
authors.initials: BA
authors.lastname: Imhof
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: s.nourshargh@qmul.ac.uk.
authors.forename: Sussan
authors.initials: S
authors.lastname: Nourshargh
mesh_terms: D000818:Animals; D001565:Benzoates / Q000008:administration & dosage; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D007365:Intercellular Junctions / Q000187:drug effects; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism*; D007975:Leukotriene B4 / Q000008:administration & dosage / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D015427:Reperfusion Injury / Q000276:immunology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000276:immunology*; D014699:Venules / Q000502:physiology; D014947:Wounds and Injuries / Q000276:immunology
chemical_list: D001565:Benzoates; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C486723:Jam3 protein, mouse; C094099:LY 293111; D016177:Macrophage-1 Antigen; D007975:Leukotriene B4; D019272:Leukocyte Elastase