title: Lactoferrin Suppresses Neutrophil Extracellular Traps Release in Inflammation.
abstract: Neutrophils are central players in the innate immune system. They generate neutrophil extracellular traps (NETs), which protect against invading pathogens but are also associated with the development of autoimmune and/or inflammatory diseases and thrombosis. Here, we report that lactoferrin, one of the components of NETs, translocated from the cytoplasm to the plasma membrane and markedly suppressed NETs release. Furthermore, exogenous lactoferrin shrunk the chromatin fibers found in released NETs, without affecting the generation of oxygen radicals, but this failed after chemical removal of the positive charge of lactoferrin, suggesting that charge-charge interactions between lactoferrin and NETs were required for this function. In a model of immune complex-induced NET formation in vivo, intravenous lactoferrin injection markedly reduced the extent of NET formation. These observations suggest that lactoferrin serves as an intrinsic inhibitor of NETs release into the circulation. Thus, lactoferrin may represent a therapeutic lead for controlling NETs release in autoimmune and/or inflammatory diseases.
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Japan; Apheresis and Dialysis Center, School of Medicine, Keio University, Japan; Department of General Medicine, School of Medicine, Keio University, Japan.
authors.forename: Koshu
authors.initials: K
authors.lastname: Okubo
authors.affiliation: Laboratory of Chemical Biology & Molecular Imaging, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Mako
authors.initials: M
authors.lastname: Kamiya
authors.affiliation: Laboratory of Chemical Biology & Molecular Imaging, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Urano
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, United States.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishi
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, United States.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Herter
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, United States.
authors.forename: Tanya
authors.initials: T
authors.lastname: Mayadas
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Japan; Research Center for Advanced Science and Technology, The University of Tokyo, Japan.
authors.forename: Daigoro
authors.initials: D
authors.lastname: Hirohama
authors.affiliation: Inflammation Program, Graduate School of Medicine, Chiba University, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Division of Food and Nutrition, Graduate School of Human Sciences, Kyoritsu Women's University, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Japan; Department of General Medicine, School of Medicine, Keio University, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Kurosawa
authors.affiliation: NRL Pharma, Inc., Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kagaya
authors.affiliation: Department of Advanced Nephrology and Regenerative Medicine, The University of Tokyo, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hishikawa
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Japan.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Japan; Research Center for Advanced Science and Technology, The University of Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Apheresis and Dialysis Center, School of Medicine, Keio University, Japan; Department of General Medicine, School of Medicine, Keio University, Japan.
authors.forename: Matsuhiko
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Japan; Apheresis and Dialysis Center, School of Medicine, Keio University, Japan; Department of General Medicine, School of Medicine, Keio University, Japan. Electronic address: jhirahashi-tky@umin.ac.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Hirahashi
mesh_terms: D000596:Amino Acids; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D065206:Extracellular Traps / Q000378:metabolism*; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007781:Lactoferrin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000596:Amino Acids; D006657:Histones; D017382:Reactive Oxygen Species; D007781:Lactoferrin; D019272:Leukocyte Elastase
keywords: Chromatin; Lactoferrin; Neutrophil extracellular traps (NETs); Oxygen radicals