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Published on: January 23, 2019
MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1
Takashi Shichita1,2,3,4,5, Minako Ito1,2, Rimpei Morita1,2
1Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.
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.
Insights
This study reveals how scavenger receptors MSR1 and MARCO clear damage-associated molecular patterns (DAMPs) to resolve sterile inflammation. Targeting these pathways, like with Am80, shows therapeutic potential for tissue injury recovery.
Area of Science:
- Immunology
- Neuroscience
- Molecular Biology
Background:
- Sterile inflammation following tissue injury is initiated by damage-associated molecular patterns (DAMPs).
- Mechanisms governing the resolution of sterile inflammation are not fully understood.
- Key DAMPs include high-mobility-group box 1 (HMGB1), peroxiredoxins (PRXs), and S100A8/S100A9.
Purpose of the Study:
- To elucidate the cellular mechanisms responsible for DAMP clearance during sterile inflammation resolution.
- To investigate the role of scavenger receptors MSR1 and MARCO in DAMP internalization.
- To explore the therapeutic potential of modulating DAMP clearance pathways.
Main Methods:
- In vitro studies using class A scavenger receptors MSR1 and MARCO for DAMP internalization.
- In vivo experiments utilizing a murine model of ischemic stroke.
- Analysis of MSR1 expression in myeloid cells and its dependence on the transcription factor Mafb.
- Assessment of the effects of combined Msr1/Marco deficiency and Mafb deficiency on inflammation and neuronal injury.
- Evaluation of the retinoic acid receptor (RAR) agonist Am80 as a therapeutic agent.
Main Results:
- Common DAMPs were internalized via scavenger receptors MSR1 and MARCO in vitro.
- MSR1 was the primary mediator of DAMP internalization in the ischemic murine brain.
- MSR1 expression in myeloid cells post-stroke depended on the transcription factor Mafb.
- Deficiency in MSR1/MARCO or Mafb led to impaired DAMP clearance, increased inflammation, and worsened neuronal injury.
- The RAR agonist Am80 enhanced Mafb and MSR1 expression, demonstrating therapeutic efficacy even 24 hours after stroke onset.
Conclusions:
- Class A scavenger receptors MSR1 and MARCO are critical for DAMP clearance.
- Mafb is a key regulator of MSR1 expression in myeloid cells during sterile inflammation.
- Targeting the Mafb-MSR1 axis with agents like Am80 offers a promising therapeutic strategy for mitigating tissue damage and inflammation after injury.
