title: Blocking neutrophil diapedesis prevents hemorrhage during thrombocytopenia.
abstract: Spontaneous organ hemorrhage is the major complication in thrombocytopenia with a potential fatal outcome. However, the exact mechanisms regulating vascular integrity are still unknown. Here, we demonstrate that neutrophils recruited to inflammatory sites are the cellular culprits inducing thrombocytopenic tissue hemorrhage. Exposure of thrombocytopenic mice to UVB light provokes cutaneous petechial bleeding. This phenomenon is also observed in immune-thrombocytopenic patients when tested for UVB tolerance. Mechanistically, we show, analyzing several inflammatory models, that it is neutrophil diapedesis through the endothelial barrier that is responsible for the bleeding defect. First, bleeding is triggered by neutrophil-mediated mechanisms, which act downstream of capturing, adhesion, and crawling on the blood vessel wall and require Gαi signaling in neutrophils. Second, mutating Y731 in the cytoplasmic tail of VE-cadherin, known to selectively affect leukocyte diapedesis, but not the induction of vascular permeability, attenuates bleeding. Third, and in line with this, simply destabilizing endothelial junctions by histamine did not trigger bleeding. We conclude that specifically targeting neutrophil diapedesis through the endothelial barrier may represent a new therapeutic avenue to prevent fatal bleeding in immune-thrombocytopenic patients.
authors.affiliation: Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Münster and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, 48149 Münster, Germany Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Münster and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, 48149 Münster, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Hillgruber
authors.affiliation: Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Münster and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, 48149 Münster, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Pöppelmann
authors.affiliation: Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Münster and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, 48149 Münster, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Weishaupt
authors.affiliation: Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Münster and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, 48149 Münster, Germany.
authors.forename: Annika Kathrin
authors.initials: AK
authors.lastname: Steingräber
authors.affiliation: Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wessel
authors.affiliation: Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Münster and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, 48149 Münster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Clinical Department of Immunology and Rheumatology, Molecular Immunology Research Unit, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: J Engelbert
authors.initials: JE
authors.lastname: Gessner
authors.affiliation: French Institute of Health and Medical Research (INSERM) U1148-Paris 7 University, Xavier Bichat Hospital, 75877 Paris, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Ho-Tin-Noé
authors.affiliation: Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany tobias.goerge@ukmuenster.de vestweb@mpi-muenster.mpg.de.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.affiliation: Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Münster and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, 48149 Münster, Germany Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Münster and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, 48149 Münster, Germany tobias.goerge@ukmuenster.de vestweb@mpi-muenster.mpg.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Goerge
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D003877:Dermatitis, Contact / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D005434:Flow Cytometry; D006470:Hemorrhage / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D006652:Histological Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense / Q000235:genetics; D009504:Neutrophils / Q000502:physiology*; D013921:Thrombocytopenia / Q000503:physiopathology*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000502:physiology*; D014466:Ultraviolet Rays; D014657:Vasculitis / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D000099152:Cadherin 5