title: MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1.
abstract: Damage-associated molecular patterns (DAMPs) trigger sterile inflammation after tissue injury, but the mechanisms underlying the resolution of inflammation remain unclear. In this study, we demonstrate that common DAMPs, such as high-mobility-group box 1 (HMGB1), peroxiredoxins (PRXs), and S100A8 and S100A9, were internalized through the class A scavenger receptors MSR1 and MARCO in vitro. In ischemic murine brain, DAMP internalization was largely mediated by MSR1. An elevation of MSR1 levels in infiltrating myeloid cells observed 3 d after experimental stroke was dependent on the transcription factor Mafb. Combined deficiency for Msr1 and Marco, or for Mafb alone, in infiltrating myeloid cells caused impaired clearance of DAMPs, more severe inflammation, and exacerbated neuronal injury in a murine model of ischemic stroke. The retinoic acid receptor (RAR) agonist Am80 increased the expression of Mafb, thereby enhancing MSR1 expression. Am80 exhibited therapeutic efficacy when administered, even at 24 h after the onset of experimental stroke. Our findings uncover cellular mechanisms contributing to DAMP clearance in resolution of the sterile inflammation triggered by tissue injury.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan.|Stroke Renaissance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shichita
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.
authors.forename: Rimpei
authors.initials: R
authors.lastname: Morita
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Komai
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Noguchi
authors.affiliation: Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ooboshi
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Koshida
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000067531:Alarmins / Q000276:immunology*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000276:immunology*; D002545:Brain Ischemia / Q000276:immunology; D064113:CRISPR-Cas Systems; D040501:Calgranulin A / Q000276:immunology; D040502:Calgranulin B / Q000276:immunology; D047369:Chromatin Immunoprecipitation; D024243:HMGB1 Protein / Q000276:immunology; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology*; D007249:Inflammation; D051258:MafB Transcription Factor / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D054464:Peroxiredoxins / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D018168:Receptors, Retinoic Acid / Q000819:agonists; D051117:Scavenger Receptors, Class A / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D020521:Stroke / Q000276:immunology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D000067531:Alarmins; D001565:Benzoates; D040501:Calgranulin A; D040502:Calgranulin B; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; C092228:Marco protein, mouse; C495140:Msr1 protein, mouse; D011971:Receptors, Immunologic; D018168:Receptors, Retinoic Acid; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; D051117:Scavenger Receptors, Class A; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D054464:Peroxiredoxins