2. Academic Validation
  3. MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1

MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1

  • Nat Med. 2017 Jun;23(6):723-732. doi: 10.1038/nm.4312.
Takashi Shichita 1 2 3 4 5,  Minako Ito 1 2,  Rimpei Morita 1 2,  Kyoko Komai 1 2,  Yoshiko Noguchi 1 2,  Hiroaki Ooboshi 6,  Ryusuke Koshida 7,  Satoru Takahashi 7,  Tatsuhiko Kodama 8,  Akihiko Yoshimura 1 2
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.
  • 2 Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.
  • 3 Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan.
  • 4 Stroke Renaissance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
  • 5 Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 6 Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
  • 7 Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
  • 8 Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
PMID: 28394332 DOI: 10.1038/nm.4312
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.

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