Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes

Russo, Antonella; Schürmann, Hendrik; Brandt, Matthias; Scholz, Katja; Matos, Anna Livia L.; Grill, David; Revenstorff, Julian; Rembrink, Max; Wulffen, Meike von; Fischer-Riepe, Lena; Hanley, Peter J.; Häcker, Hans; Prünster, Monika; Sanchez-Madrid, Francisco; Hermann, Sven; Klotz, Luisa; Gerke, Volker; Betz, Timo; Vogl, Thomas und Roth, Johannes (2022): Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes. In: Advanced Science, Bd. 9, Nr. 36, 2201505

Abstract

Mechanisms keeping leukocytes distant of local inflammatory processes in a resting state despite systemic release of inflammatory triggers are a pivotal requirement for avoidance of overwhelming inflammation but are ill defined. Dimers of the alarmin S100A8/S100A9 activate Toll-like receptor-4 (TLR4) but extracellular calcium concentrations induce S100A8/S100A9-tetramers preventing TLR4-binding and limiting their inflammatory activity. So far, only antimicrobial functions of released S100A8/S100A9-tetramers (calprotectin) are described. It is demonstrated that extracellular S100A8/S100A9 tetramers significantly dampen monocyte dynamics as adhesion, migration, and traction force generation in vitro and immigration of monocytes in a cutaneous granuloma model and inflammatory activity in a model of irritant contact dermatitis in vivo. Interestingly, these effects are not mediated by the well-known binding of S100A8/S100A9-dimers to TLR-4 but specifically mediated by S100A8/S100A9-tetramer interaction with CD69. Thus, the quaternary structure of these S100-proteins determines distinct and even antagonistic effects mediated by different receptors. As S100A8/S100A9 are released primarily as dimers and subsequently associate to tetramers in the high extracellular calcium milieu, the same molecules promote inflammation locally (S100-dimer/TLR4) but simultaneously protect the wider environment from overwhelming inflammation (S100-tetramer/CD69).

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 449437943
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 449437943
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 194468054
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 194468054