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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents



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ID: 717309.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
Blocking neutrophil diapedesis prevents hemorrhage during thrombocytopenia
Authors:Hillgruber, C.; Poppelmann, B.; Weishaupt, C.; Steingraber, A. K.; Wessel, F.; Berdel, W. E.; Gessner, J. E.; Ho-Tin-Noe, B.; Vestweber, D.; Goerge, T.
Date of Publication (YYYY-MM-DD):2015-07-27
Title of Journal:J Exp Med
Volume:212
Issue / Number:8
Start Page:1255
End Page:1266
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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 Galphai 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.
Free Keywords:Analysis of Variance; Animals; Antigens, CD/*genetics; Cadherins/*genetics; Dermatitis, Contact/etiology/immunology/*pathology; Flow Cytometry; Hemorrhage/etiology/*physiopathology/prevention & control; Histological Techniques; Humans; Mice; Mice, Inbred C57BL; Mutation, Missense/genetics; Neutrophils/*physiology; Thrombocytopenia/*physiopathology; Transendothelial and Transepithelial Migration/drug effects/*physiology; Ultraviolet Rays; Vasculitis/etiology/immunology/*pathology
External Publication Status:published
Document Type:Article
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Munster and Interdisciplinary Center for Clinical Research (IZKF), University of Munster, 48149 Munster, Germany. Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany. Clinical Department of Immunology and Rheumatology, Molecular Immunology Research Unit, Hannover Medical School, 30625 Hannover, Germany. French Institute of Health and Medical Research (INSERM) U1148-Paris 7 University, Xavier Bichat Hospital, 75877 Paris, France. Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany tobias.goerge@ukmuenster.de vestweb@mpi-muenster.mpg.de. Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Munster and Interdisciplinary Center for Clinical Research (IZKF), University of Munster, 48149 Munster, Germany Department of Dermatology and Department of Medicine A-Hematology and Oncology, University Hospital of Munster and Interdisciplinary Center for Clinical Research (IZKF), University of Munster, 48149 Munster, Germany tobias.goerge@ukmuenster.de vestweb@mpi-muenster.mpg.de.
Identifiers:ISSN:1540-9538 (Electronic) 0022-1007 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/26169941 [ID No:2]
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