title: IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs.
abstract: Intravital visualization of thrombopoiesis revealed that formation of proplatelets, which are cytoplasmic protrusions in bone marrow megakaryocytes (MKs), is dominant in the steady state. However, it was unclear whether this is the only path to platelet biogenesis. We have identified an alternative MK rupture, which entails rapid cytoplasmic fragmentation and release of much larger numbers of platelets, primarily into blood vessels, which is morphologically and temporally different than typical FasL-induced apoptosis. Serum levels of the inflammatory cytokine IL-1α were acutely elevated after platelet loss or administration of an inflammatory stimulus to mice, whereas the MK-regulator thrombopoietin (TPO) was not elevated. Moreover, IL-1α administration rapidly induced MK rupture-dependent thrombopoiesis and increased platelet counts. IL-1α-IL-1R1 signaling activated caspase-3, which reduced plasma membrane stability and appeared to inhibit regulated tubulin expression and proplatelet formation, and ultimately led to MK rupture. Collectively, it appears the balance between TPO and IL-1α determines the MK cellular programming for thrombopoiesis in response to acute and chronic platelet needs.
authors.affiliation: Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Computational Diagnostic Radiology and Preventive Medicine, Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo 113-8654, Japan Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Computational Diagnostic Radiology and Preventive Medicine, Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo 113-8654, Japan Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Saitama 332-0012, Japan snishi-tky@umin.ac.jp kojieto@cira.kyoto-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Computational Diagnostic Radiology and Preventive Medicine, Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo 113-8654, Japan Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Computational Diagnostic Radiology and Preventive Medicine, Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Nagasaki
authors.affiliation: Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya 460-001, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.affiliation: Department of Anatomy, Ultrastructural Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawaguchi
authors.affiliation: Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Sakata
authors.affiliation: Web Solution Group, IMAGICA Imageworks, Tokyo 141-0022, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sakaguchi
authors.affiliation: Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ohmori
authors.affiliation: Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Computational Diagnostic Radiology and Preventive Medicine, Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Vascular Biology Program at Boston Children's Hospital, Harvard Medical School, Boston, MA 02215.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
authors.affiliation: Internal medicine, Social Insurance Central General Hospital, Tokyo 105-8330, Japan.
authors.forename: Tomiko
authors.initials: T
authors.lastname: Ryu
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Takayama
authors.affiliation: Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Computational Diagnostic Radiology and Preventive Medicine, Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo 113-8654, Japan Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Computational Diagnostic Radiology and Preventive Medicine, Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Computational Diagnostic Radiology and Preventive Medicine, Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo 113-8654, Japan Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Computational Diagnostic Radiology and Preventive Medicine, Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan snishi-tky@umin.ac.jp kojieto@cira.kyoto-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Eto
authors.affiliation: Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism; D034061:Thrombopoiesis / Q000502:physiology*; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C583355:IL1R1 protein, mouse; D053582:Interleukin-1alpha; D053573:Receptors, Interleukin-1 Type I; D013926:Thrombopoietin; C505409:Casp3 protein, mouse; D053148:Caspase 3