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Russo, Antonella; Schürmann, Hendrik; Brandt, Matthias; Scholz, Katja; Matos, Anna Livia L.; Grill, David; Revenstorff, Julian; Rembrink, Maximilian; von Wulffen, Meike; Fischer‐Riepe, Lena; Hanley, Peter J.; Häcker, Hans; Prünster, Monika; Sánchez‐Madrid, Francisco; Hermann, Sven; Klotz, Luisa; Gerke, Volker; Betz, Timo; Vogl, Thomas; Roth, Johannes

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

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  • Media type: E-Article
  • Title: Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes
  • Contributor: Russo, Antonella; Schürmann, Hendrik; Brandt, Matthias; Scholz, Katja; Matos, Anna Livia L.; Grill, David; Revenstorff, Julian; Rembrink, Maximilian; von Wulffen, Meike; Fischer‐Riepe, Lena; Hanley, Peter J.; Häcker, Hans; Prünster, Monika; Sánchez‐Madrid, Francisco; Hermann, Sven; Klotz, Luisa; Gerke, Volker; Betz, Timo; Vogl, Thomas; Roth, Johannes
  • imprint: Wiley, 2022
  • Published in: Advanced Science
  • Language: English
  • DOI: 10.1002/advs.202201505
  • ISSN: 2198-3844
  • Keywords: General Physics and Astronomy ; General Engineering ; Biochemistry, Genetics and Molecular Biology (miscellaneous) ; General Materials Science ; General Chemical Engineering ; Medicine (miscellaneous)
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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).</jats:p>
  • Access State: Open Access