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Dimers of the alarmin S100A8\/S100A9 activate Toll\u2010like receptor\u20104 (TLR4) but extracellular calcium concentrations induce S100A8\/S100A9\u2010tetramers preventing TLR4\u2010binding and limiting their inflammatory activity. So far, only antimicrobial functions of released S100A8\/S100A9\u2010tetramers (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\u2010known binding of S100A8\/S100A9\u2010dimers to TLR\u20104 but specifically mediated by S100A8\/S100A9\u2010tetramer interaction with CD69. Thus, the quaternary structure of these S100\u2010proteins 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\u2010dimer\/TLR4) but simultaneously protect the wider environment from overwhelming inflammation (S100\u2010tetramer\/CD69).<\/jats:p>","DOI":"10.1002\/advs.202201505","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T23:22:37Z","timestamp":1667172157000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Alarming and Calming: Opposing Roles of S100A8\/S100A9 Dimers and Tetramers on Monocytes"],"prefix":"10.1002","volume":"9","author":[{"given":"Antonella","family":"Russo","sequence":"first","affiliation":[{"name":"Institute of Immunology University of M\u00fcnster  48149 M\u00fcnster Germany"},{"name":"Cells in Motion Interfaculty Centre University of M\u00fcnster  48149 M\u00fcnster 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