title: Platelets induce apoptosis via membrane-bound FasL.
abstract: After tissue injury, both wound sealing and apoptosis contribute to restoration of tissue integrity and functionality. Although the role of platelets (PLTs) for wound closure and induction of regenerative processes is well established, the knowledge about their contribution to apoptosis is incomplete. Here, we show that PLTs present the death receptor Fas ligand (FasL) on their surface after activation. Activated PLTs as well as the isolated membrane fraction of activated PLTs but not of resting PLTs induced apoptosis in a dose-dependent manner in primary murine neuronal cells, human neuroblastoma cells, and mouse embryonic fibroblasts. Membrane protein from PLTs lacking membrane-bound FasL (FasL(△m/△m)) failed to induce apoptosis. Bax/Bak-mediated mitochondrial apoptosis signaling in target cells was not required for PLT-induced cell death, but increased the apoptotic response to PLT-induced Fas signaling. In vivo, PLT depletion significantly reduced apoptosis in a stroke model and an inflammation-independent model of N-methyl-d-aspartic acid-induced retinal apoptosis. Furthermore, experiments using PLT-specific PF4Cre(+) FasL(fl/fl) mice demonstrated a role of PLT-derived FasL for tissue apoptosis. Because apoptosis secondary to injury prevents inflammation, our findings describe a novel mechanism on how PLTs contribute to tissue homeostasis.
authors.affiliation: Department of Cardiovascular Medicine, Section for Cardioimmunology, and Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Rebecca I
authors.initials: RI
authors.lastname: Schleicher
authors.affiliation: Institute for Biochemistry and Molecular Biology, Centre for Biochemistry and Molecular Cell Research (ZBMZ), and Faculty of Biology, University of Freiburg, Freiburg, Germany;
authors.forename: Frank
authors.initials: F
authors.lastname: Reichenbach
authors.affiliation: Department of Neurology, University Hospital Wuerzburg, Wuerzburg, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: National Eye Institute, Bethesda, MD;
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Cardiovascular Surgery, University Hospital, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Mario
authors.initials: M
authors.lastname: Lescan
authors.affiliation: Institute for Biochemistry and Molecular Biology, Centre for Biochemistry and Molecular Cell Research (ZBMZ), and.
authors.forename: Franziska
authors.initials: F
authors.lastname: Todt
authors.affiliation: Department of Neurology and Institute of Physiology (Neuropathophysiology), University of Muenster, Muenster, Germany;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Göbel
authors.affiliation: Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany;
authors.forename: Ingo
authors.initials: I
authors.lastname: Hilgendorf
authors.affiliation: Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Geisler
authors.affiliation: Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Axel
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Department of Cardiovascular Medicine, Section for Cardioimmunology, and Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Marcus
authors.initials: M
authors.lastname: Olbrich
authors.affiliation: Department of Dermatology, University Hospital, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Institute for Molecular Medicine, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wesselborg
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;
authors.forename: Lorraine
authors.initials: L
authors.lastname: O'Reilly
authors.affiliation: Department of Neurology and Institute of Physiology (Neuropathophysiology), University of Muenster, Muenster, Germany;
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen and German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.affiliation: Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China; and.
authors.forename: Xuri
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurology, University Hospital Wuerzburg, Wuerzburg, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.affiliation: Institute for Biochemistry and Molecular Biology, Centre for Biochemistry and Molecular Cell Research (ZBMZ), and Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Edlich
authors.affiliation: Department of Cardiovascular Medicine, Section for Cardioimmunology, and Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tuebingen, Germany;
authors.forename: Harald F
authors.initials: HF
authors.lastname: Langer
mesh_terms: D000818:Animals; D017209:Apoptosis; D001792:Blood Platelets / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D015539:Platelet Activation; D020521:Stroke / Q000276:immunology / Q000473:pathology
chemical_list: D053222:Fas Ligand Protein