Stroke Literature Synopses: Basic Science

Shichita et al (MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1. Nat Med. 2017;23:723–732. doi: 10.1038/nm.4312) examined the mechanisms of clearance of DAMPs after stroke. High-mobility-group box 1 (HMGB1), peroxiredoxins, and S100A8/A9 proteins are well-characterized DAMPs that are involved in brain injury. The authors isolated cells from day 3 postischemic mouse brain (male C57BL/6; 8–14 weeks; 60 minutes middle cerebral artery occlusion by filament insertion) and incubate the cells with fluorescence-labeled recombinant peroxiredoxins, HMGB1, and S100A8/A9. Immunostaining and fluorescence-activated cell sorter experiments confirmed that those DAMPs were selectively internalized by infiltrating mononuclear phagocytes. Then, using a macrophage-like cell line RAW264.7, the authors established mutant clones that were deficient in the internalization of those DAMPs. By comparing the gene expression profiles of parental RAW264.7 and the mutant lines, MSR1 (macrophage scavenger receptor 1) was identified to play a critical role in DAMP internalization. In ischemic mouse brain, DAMP internalization was indeed mediated by MSR1, and the elevation of MSR1 expression in infiltrating myeloid cells after stroke in mice was dependent on the transcription factor Mafb. Importantly, mice with Mafb deficiency in macrophage/neutrophil (Lysm-Cre:Mafb-flox/flox mice) showed larger amounts of DAMPs in brain and worse stroke outcomes compared with wild-type mice. Because the retinoic acid receptor agonist Am80, which can increase the expression of Mafb, exhibited efficacy in these mouse stroke models, enhancing DAMP clearance may be a therapeutic target for ischemic stroke.