{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:49:49Z","timestamp":1792522189885,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T00:00:00Z","timestamp":1641859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["668303"],"award-info":[{"award-number":["668303"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Neutrophils are the most abundant innate immune cells in the circulation and they are the first cells recruited to sites of infection or inflammation. Almost half of the intracellular protein content in neutrophils consists of S100A8 and S100A9, though there has been controversy about their actual localization. Once released extracellularly, these proteins are thought to act as damage-associated molecular patterns (DAMPs), though their mechanism of action is not well understood. These S100 proteins mainly form heterodimers (S100A8\/A9, also known as calprotectin) and this heterocomplex is recognized as a useful biomarker for several inflammatory diseases. We observed that S100A8\/A9 is highly present in the cytoplasmic fraction of neutrophils and is not part of the granule content. Furthermore, we found that S100A8\/A9 was not released in parallel with granular content but upon the formation of neutrophil extracellular traps (NETs). Accordingly, neutrophils of patients with chronic granulomatous disease, who are deficient in phorbol 12-myristate 13-acetate (PMA)-induced NETosis, did not release S100A8\/A9 upon PMA stimulation. Moreover, we purified S100A8\/A9 from the cytoplasmic fraction of neutrophils and found that S100A8\/A9 could induce neutrophil activation, including adhesion and CD11b upregulation, indicating that this DAMP might amplify neutrophil activation.<\/jats:p>","DOI":"10.3390\/cells11020236","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T14:05:07Z","timestamp":1641909907000},"page":"236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":230,"title":["S100A8\/A9 Is a Marker for the Release of Neutrophil Extracellular Traps and Induces Neutrophil Activation"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4961-0155","authenticated-orcid":false,"given":"Evelien G. G.","family":"Sprenkeler","sequence":"first","affiliation":[{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam University Medical Center (AUMC), University of Amsterdam, 1066 CX Amsterdam, The Netherlands"},{"name":"Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children\u2019s Hospital, AUMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Zandstra","sequence":"additional","affiliation":[{"name":"Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children\u2019s Hospital, AUMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Immunopathology, AUMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7162-9277","authenticated-orcid":false,"given":"Nadine D.","family":"van Kleef","sequence":"additional","affiliation":[{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam University Medical Center (AUMC), University of Amsterdam, 1066 CX Amsterdam, The Netherlands"},{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Immunopathology, AUMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Goetschalckx","sequence":"additional","affiliation":[{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam University Medical Center (AUMC), University of Amsterdam, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibian","family":"Verstegen","sequence":"additional","affiliation":[{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam University Medical Center (AUMC), University of Amsterdam, 1066 CX Amsterdam, The Netherlands"},{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Immunopathology, AUMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathelijn E. M.","family":"Aarts","sequence":"additional","affiliation":[{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam University Medical Center (AUMC), University of Amsterdam, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Janssen","sequence":"additional","affiliation":[{"name":"Division of Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton T. J.","family":"Tool","sequence":"additional","affiliation":[{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam University Medical Center (AUMC), University of Amsterdam, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"van Mierlo","sequence":"additional","affiliation":[{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Immunopathology, AUMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"van Bruggen","sequence":"additional","affiliation":[{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam University Medical Center (AUMC), University of Amsterdam, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7759-9897","authenticated-orcid":false,"given":"Ilse","family":"Jongerius","sequence":"additional","affiliation":[{"name":"Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children\u2019s Hospital, AUMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Immunopathology, AUMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taco W.","family":"Kuijpers","sequence":"additional","affiliation":[{"name":"Sanquin Research and Laboratory Services and Landsteiner Laboratory, Department of Molecular Hematology, Amsterdam University Medical Center (AUMC), University of Amsterdam, 1066 CX Amsterdam, The Netherlands"},{"name":"Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children\u2019s Hospital, AUMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.immuni.2010.11.011","article-title":"Neutrophils, from marrow to microbes","volume":"33","author":"Borregaard","year":"2010","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41577-019-0215-7","article-title":"Damp-sensing receptors in sterile inflammation and inflammatory diseases","volume":"20","author":"Gong","year":"2020","journal-title":"Nat. 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