title: Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation.
abstract: Inflammatory cell recruitment to local sites of tissue injury and/or infection is controlled by a plethora of signalling processes influencing cell-to-cell interactions between the vascular endothelial cells (ECs) in post-capillary venules and circulating leukocytes. Recently, ATP-sensitive P2Y purinergic receptors have emerged as downstream regulators of EC activation in vascular inflammation. However, the mechanism(s) regulating cellular ATP release in this response remains elusive. Here we report that the ATP-release channel Pannexin1 (Panx1) opens downstream of EC activation by TNF-α. This process involves activation of type-1 TNF receptors, recruitment of Src family kinases (SFK) and SFK-dependent phosphorylation of Panx1. Using an inducible, EC-specific Panx1 knockout mouse line, we report a previously unidentified role for Panx1 channels in promoting leukocyte adhesion and emigration through the venous wall during acute systemic inflammation, placing Panx1 channels at the centre of cytokine crosstalk with purinergic signalling in the endothelium.
authors.affiliation: 1] Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA [2] Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Lohman
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Los Angeles 71130, USA.
authors.forename: Igor L
authors.initials: IL
authors.lastname: Leskov
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Butcher
authors.affiliation: British Heart Foundation Cardiovascular Research Centre, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Johnstone
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Los Angeles 71130, USA.
authors.forename: Tara A
authors.initials: TA
authors.lastname: Stokes
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Begandt
authors.affiliation: 1] Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA [2] Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Leon J
authors.initials: LJ
authors.lastname: DeLalio
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Best
authors.affiliation: Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Silvia
authors.identifier: 0000000348295517
authors.initials: S
authors.lastname: Penuela
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Los Angeles 71130, USA.
authors.forename: Karen Y
authors.initials: KY
authors.lastname: Stokes
authors.affiliation: 1] Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA [2] Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Brant E
authors.initials: BE
authors.lastname: Isakson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D017630:Connexins / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D057705:Transendothelial and Transepithelial Migration; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D014699:Venules / Q000276:immunology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; C492764:PANX1 protein, human; C503631:Panx1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D019061:src-Family Kinases