title: Neutrophils recruited by chemoattractants in vivo induce microvascular plasma protein leakage through secretion of TNF.
abstract: Microvascular plasma protein leakage is an essential component of the inflammatory response and serves an important function in local host defense and tissue repair. Mediators such as histamine and bradykinin act directly on venules to increase the permeability of endothelial cell (EC) junctions. Neutrophil chemoattractants also induce leakage, a response that is dependent on neutrophil adhesion to ECs, but the underlying mechanism has proved elusive. Through application of confocal intravital microscopy to the mouse cremaster muscle, we show that neutrophils responding to chemoattractants release TNF when in close proximity of EC junctions. In vitro, neutrophils adherent to ICAM-1 or ICAM-2 rapidly released TNF in response to LTB4, C5a, and KC. Further, in TNFR(-/-) mice, neutrophils accumulated normally in response to chemoattractants administered to the cremaster muscle or dorsal skin, but neutrophil-dependent plasma protein leakage was abolished. Similar results were obtained in chimeric mice deficient in leukocyte TNF. A locally injected TNF blocking antibody was also able to inhibit neutrophil-dependent plasma leakage, but had no effect on the response induced by bradykinin. The results suggest that TNF mediates neutrophil-dependent microvascular leakage. This mechanism may contribute to the effects of TNF inhibitors in inflammatory diseases and indicates possible applications in life-threatening acute edema.
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, England, UK.
authors.forename: Michaela
authors.initials: M
authors.lastname: Finsterbusch
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, England, UK.
authors.forename: Mathieu-Benoit
authors.initials: MB
authors.lastname: Voisin
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, England, 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, London E1 4NS, England, UK National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, England, UK.
authors.forename: Timothy John
authors.initials: TJ
authors.lastname: Williams
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, England, UK s.nourshargh@qmul.ac.uk.
authors.forename: Sussan
authors.initials: S
authors.lastname: Nourshargh
mesh_terms: D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD; D002199:Capillary Permeability / Q000235:genetics / Q000276:immunology*; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology*; D015936:Complement C5a / Q000235:genetics / Q000276:immunology*; D004487:Edema / Q000235:genetics / Q000276:immunology / Q000473:pathology; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D007365:Intercellular Junctions / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007975:Leukotriene B4 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D010949:Plasma; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C480027:ICAM-2 protein, mouse; C090509:Icam1 protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007975:Leukotriene B4; D015936:Complement C5a