RRC ID 49232
Author Shichita T, Ito M, Morita R, Komai K, Noguchi Y, Ooboshi H, Koshida R, Takahashi S, Kodama T, Yoshimura A.
Title MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1.
Journal Nat Med
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.
Volume 23(6)
Pages 723-732
Published 2017-6-1
DOI 10.1038/nm.4312
PII nm.4312
PMID 28394332
MeSH Alarmins / immunology* Animals Benzoates / pharmacology Brain / drug effects Brain / immunology* Brain Ischemia / immunology CRISPR-Cas Systems Calgranulin A / immunology Calgranulin B / immunology Chromatin Immunoprecipitation HMGB1 Protein / immunology Infarction, Middle Cerebral Artery / immunology* Inflammation MafB Transcription Factor / drug effects MafB Transcription Factor / genetics MafB Transcription Factor / immunology* Mice Myeloid Cells / immunology* Myeloid Cells / metabolism Peroxiredoxins / immunology Receptors, Immunologic / genetics Receptors, Immunologic / immunology* Receptors, Retinoic Acid / agonists Scavenger Receptors, Class A / drug effects Scavenger Receptors, Class A / genetics Scavenger Receptors, Class A / immunology* Stroke / immunology Tetrahydronaphthalenes / pharmacology
IF 36.13
Times Cited 48
DNA material CSII-EF-MCS-IRES2-Venus (RDB04384) pCMV-VSV-G-RSV-Rev (RDB04393).
Human and Animal Cells 293T(RCB2202)