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    MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1.
    Nat Med 2017 Jun 10;23(6):723-732. Epub 2017 Apr 10.
    Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.
    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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    Role of scavenger receptors as damage-associated molecular pattern receptors in Toll-like receptor activation.
    Int Immunol 2017 Feb;29(2):59-70
    Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
    Damage-associated molecular patterns (DAMPs) have been implicated in sterile inflammation in various tissue injuries. High-mobility group box 1 (HMGB1) is a representative DAMP, and has been shown to transmit signals through receptors for advanced glycation end products (RAGEs) and TLRs, including TLR2 and TLR4. HMGB1 does not, however, bind to TLRs with high affinity; therefore, the mechanism of HMGB1-mediated TLR activation remains unclear. Read More
    [DAMPs (damage-associated molecular patterns) and inflammation].
    Nihon Rinsho 2016 Apr;74(4):573-8
    Post-ischemic inflammation is re-appraised as an important player in the progression of ischemic stroke. Activation of inflammatory cells via Toll-like receptor 2 (TLR2) and TLR4 is caused by several damage-associated molecular patterns (DAMPs), including high mobility group box-1 (HMGB-1) and heat shock proteins. We have recently found that peroxiredoxin (Prx) is one of the strong DAMPs and activates infiltrating macrophages in brain ischemia. Read More
    Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain.
    Nat Med 2012 Jun;18(6):911-7
    Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.
    Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. Read More
    S100A9 induced inflammatory responses are mediated by distinct damage associated molecular patterns (DAMP) receptors in vitro and in vivo.
    PLoS One 2015 23;10(2):e0115828. Epub 2015 Feb 23.
    MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland 20878, United States of America.
    Release of endogenous damage associated molecular patterns (DAMPs), including members of the S100 family, are associated with infection, cellular stress, tissue damage and cancer. The extracellular functions of this family of calcium binding proteins, particularly S100A8, S100A9 and S100A12, are being delineated. They appear to mediate their functions via receptor for advanced glycation endproducts (RAGE) or TLR4, but there remains considerable uncertainty over the relative physiological roles of these DAMPs and their pattern recognition receptors. Read More