Blocking neutrophil diapedesis prevents hemorrhage during thrombocytopenia.

Autor:	Hillgruber C; 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., Pöppelmann B; 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., Weishaupt C; 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., Steingräber AK; 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., Wessel F; Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany., Berdel WE; 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., Gessner JE; Clinical Department of Immunology and Rheumatology, Molecular Immunology Research Unit, Hannover Medical School, 30625 Hannover, Germany., Ho-Tin-Noé B; French Institute of Health and Medical Research (INSERM) U1148-Paris 7 University, Xavier Bichat Hospital, 75877 Paris, France., Vestweber D; Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany tobias.goerge@ukmuenster.de vestweb@mpi-muenster.mpg.de., Goerge T; 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.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2015 Jul 27; Vol. 212 (8), pp. 1255-66. Date of Electronic Publication: 2015 Jul 13.
DOI:	10.1084/jem.20142076
Abstrakt:	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. (© 2015 Hillgruber et al.)
Databáze:	MEDLINE
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