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oai:repisalud.isciii.es:20.500.12105/158182024-09-21T10:44:11Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Russo, Antonella author Schürmann, Hendrik author Brandt, Matthias author Scholz, Katja author Matos, Anna Livia L author Grill, David author Revenstorff, Julian author Rembrink, Maximilian author von Wulffen, Meike author Fischer-Riepe, Lena author Hanley, Peter J author Häcker, Hans author Prünster, Monika author Sánchez-Madrid, Francisco author Hermann, Sven author Klotz, Luisa author Gerke, Volker author Betz, Timo author Vogl, Thomas author Roth, Johannes author 2022-12 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). Adv Sci (Weinh). 2022 Dec;9(36):e2201505 http://hdl.handle.net/20.500.12105/15818 36310133 10.1002/advs.202201505 2198-3844 Advanced science (Weinheim, Baden-Wurttemberg, Germany) Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes.