{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Russo A"],"funding":["CRC TRR332","Interdisciplinary Center of Clinical Research","CRU342","RO1190/14-1","German Research Foundation CRC1009"],"pagination":["e2201505"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9798971"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["9(36)"],"pubmed_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)."],"journal":["Advanced science (Weinheim, Baden-Wurttemberg, Germany)"],"pubmed_title":["Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes."],"pmcid":["PMC9798971"],"funding_grant_id":["P3","B5","Ro2/023/19","Vo2/011/19","C7","P5","B8","B9","Z2"],"pubmed_authors":["Scholz K","Fischer-Riepe L","Hacker H","Roth J","Schurmann H","Rembrink M","Prunster M","Gerke V","Brandt M","Matos ALL","Revenstorff J","Sanchez-Madrid F","Klotz L","Betz T","Hermann S","Russo A","Grill D","von Wulffen M","Hanley PJ","Vogl T"],"additional_accession":[]},"is_claimable":false,"name":"Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes.","description":"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).","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2025-04-22T04:30:41.748Z","creation":"2025-04-05T21:00:40.922Z"},"accession":"S-EPMC9798971","cross_references":{"pubmed":["36310133"],"doi":["10.1002/advs.202201505"]}}