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Disulfide and Fully Reduced HMGB1 Induce Different Macrophage Polarization and Migration Patterns
Henna Salo1, Heshuang Qu1, Dimitra Mitsiou1
1Department of Medicine, Solna, Rheumatology Unit, Centre for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
Biomolecules
|June 2, 2021
Summary
High-mobility group box 1 (HMGB1) protein isoforms, disulfide HMGB1 (dsHMGB1) and fully reduced HMGB1 (frHMGB1), induce distinct macrophage polarization. DsHMGB1 uniquely drives pro-inflammatory cytokine secretion and cell migration via toll-like receptor 4.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Macrophage plasticity allows diverse functions, from inflammation to repair.
- High-mobility group box 1 (HMGB1) protein can induce macrophage polarization into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes.
- HMGB1's redox state influences its biological activity and interaction with innate immunity pathways.
Purpose of the Study:
- To investigate the distinct macrophage polarization phenotypes induced by different HMGB1 redox isoforms.
- To elucidate the mechanisms underlying HMGB1-mediated macrophage responses, including cytokine secretion and migration.
- To determine the role of toll-like receptor 4 (TLR4) in dsHMGB1-induced macrophage activation.
Main Methods:
- Murine bone-marrow-derived macrophages (BMDMs) were stimulated with disulfide HMGB1 (dsHMGB1) and fully reduced HMGB1 (frHMGB1).
- Macrophage polarization was assessed by analyzing cytokine secretion profiles.
- Cell migration was evaluated using scratch assays.
- The involvement of TLR4 was investigated in dsHMGB1-stimulated macrophages.
Main Results:
- Disulfide HMGB1 (dsHMGB1) induced a unique macrophage phenotype characterized by pro-inflammatory cytokine secretion, distinct from classical M1 polarization.
- Fully reduced HMGB1 (frHMGB1) did not induce significant macrophage polarization.
- Both dsHMGB1 and frHMGB1 stimulated macrophage migration, with dsHMGB1's effects on cytokine secretion and motility primarily mediated by TLR4.
- DsHMGB1 induced a unique phenotype that differs from classical pro-inflammatory macrophages.
Conclusions:
- HMGB1 redox isoforms differentially regulate macrophage polarization and function.
- DsHMGB1 induces a unique pro-inflammatory macrophage phenotype via TLR4, impacting cytokine secretion and cell migration.
- These findings highlight the nuanced role of HMGB1 in modulating innate immune responses and macrophage plasticity.
