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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We thank N. Shiino, A. Ino, and M. Asakawa for their technical assistance and H. Yao for his technical advice on the MCAO model. Msr1/Marco-deficient mice were kindly provided by K. Tryggvason (Duke–NUS Medical School). This work was supported by PRESTO from the Japan Science and Technology Agency (T.S.), a Grant-in-Aid for Scientific Research on Innovative Areas (Homeostatic regulation by various types of cell death) (15H01387) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) (T.S.), JSPS KAKENHI Grants-in-Aid for Young Scientists (B) (26870571) (T.S.) and (S) (25221305) (A.Y.), Advanced Research & Development Programs for Medical Innovation (AMED-CREST) (A.Y.), a Toray Science and Technology Grant (T.S.), the Takeda Science Foundation (T.S.), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (T.S.), a Japan Heart Foundation Research Grant (T.S.), the SENSHIN Medical Research Foundation (A.Y.), Keio Gijuku Academic Developmental Funds (A.Y.), and Open Research for Young Academics and Specialists from MEXT (A.Y.).
The authors declare no competing financial interests.
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Shichita, T., Ito, M., Morita, R. et al. MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1. Nat Med 23, 723–732 (2017). https://doi.org/10.1038/nm.4312
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