{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:28:35Z","timestamp":1792452515047,"version":"4.5.0"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T00:00:00Z","timestamp":1620777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation (DFG)","award":["KL 595\/2-3"],"award-info":[{"award-number":["KL 595\/2-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Murine models of coxsackievirus B3 (CVB3)-induced myocarditis well represent the different outcomes of this inflammatory heart disease. Previously, we found that CVB3-infected A.BY\/SnJ mice, susceptible for severe acute and chronic myocarditis, have lower natural killer (NK) cell levels than C57BL\/6 mice, with mild acute myocarditis. There is evidence that myeloid-derived suppressor cells (MDSC) may inhibit NK cells, influencing the course of myocarditis. To investigate the MDSC\/NK interrelationship in acute myocarditis, we used CVB3-infected A.BY\/SnJ mice. Compared to non-infected mice, we found increased cell numbers of MDSC in the spleen and heart of CVB3-infected A.BY\/SnJ mice. In parallel, S100A8 and S100A9 were increased in the heart, spleen, and especially in splenic MDSC cells compared to non-infected mice. In vitro experiments provided evidence that MDSC disrupt cytotoxic NK cell function upon co-culturing with MDSC. MDSC-specific depletion by an anti-Ly6G antibody led to a significant reduction in the virus load and injury in hearts of infected animals. The decreased cardiac damage in MDSC-depleted mice was associated with fewer Mac3+ macrophages and CD3+ T lymphocytes and a reduced cardiac expression of S100A8, S100A9, IL-1\u03b2, IL-6, and TNF-\u03b1. In conclusion, impairment of functional NK cells by MDSC promotes the development of chronic CVB3 myocarditis in A.BY\/SnJ mice.<\/jats:p>","DOI":"10.3390\/v13050889","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T03:08:12Z","timestamp":1620875292000},"page":"889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Myeloid-Derived Suppressor Cells Restrain Natural Killer Cell Activity in Acute Coxsackievirus B3-Induced Myocarditis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4461-8614","authenticated-orcid":false,"given":"Irene","family":"M\u00fcller","sequence":"first","affiliation":[{"name":"BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit\u00e9-Universit\u00e4tsmedizin Berlin, 10017 Berlin, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10017 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8715-3901","authenticated-orcid":false,"given":"Lisa","family":"Janson","sequence":"additional","affiliation":[{"name":"Cardiopathology, Institute for Pathology and Neuropathology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Sauter","sequence":"additional","affiliation":[{"name":"Cardiopathology, Institute for Pathology and Neuropathology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Pappritz","sequence":"additional","affiliation":[{"name":"BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit\u00e9-Universit\u00e4tsmedizin Berlin, 10017 Berlin, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10017 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie Van","family":"Linthout","sequence":"additional","affiliation":[{"name":"BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit\u00e9-Universit\u00e4tsmedizin Berlin, 10017 Berlin, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10017 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Tsch\u00f6pe","sequence":"additional","affiliation":[{"name":"BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit\u00e9-Universit\u00e4tsmedizin Berlin, 10017 Berlin, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10017 Berlin, Germany"},{"name":"Department of Cardiology, Campus Virchow Clinic, Charit\u00e9-Universit\u00e4tsmedizin Berlin, 10017 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0203-2498","authenticated-orcid":false,"given":"Karin","family":"Klingel","sequence":"additional","affiliation":[{"name":"Cardiopathology, Institute for Pathology and Neuropathology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1093\/eurheartj\/eht210","article-title":"Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases","volume":"34","author":"Caforio","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1161\/CIRCRESAHA.114.304951","article-title":"Lack in treatment options for virus-induced inflammatory cardiomyopathy: Can iPS-derived cardiomyocytes close the gap?","volume":"115","author":"Tschope","year":"2014","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1146\/annurev.pathmechdis.3.121806.151534","article-title":"Molecular biology and pathogenesis of viral myocarditis","volume":"3","author":"Esfandiarei","year":"2008","journal-title":"Annu. Rev. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s41569-020-00435-x","article-title":"Myocarditis and inflammatory cardiomyopathy: Current evidence and future directions","volume":"18","author":"Tschope","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/path.4369","article-title":"The activating receptor NKG2D of natural killer cells promotes resistance against enterovirus-mediated inflammatory cardiomyopathy","volume":"234","author":"Klingel","year":"2014","journal-title":"J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8200","DOI":"10.4049\/jimmunol.175.12.8200","article-title":"CD11b+\/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1beta-secreting cells","volume":"175","author":"Song","year":"2005","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.4049\/jimmunol.1200584","article-title":"NK cell response to vaccinia virus is regulated by myeloid-derived suppressor cells","volume":"189","author":"Fortin","year":"2012","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/imr.12084","article-title":"Myeloid-derived suppressor cells: The dark knight or the joker in viral infections?","volume":"255","author":"Goh","year":"2013","journal-title":"Immunol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"352","DOI":"10.2119\/molmed.2009.00035","article-title":"Regulatory NK-cell functions in inflammation and autoimmunity","volume":"15","author":"Lunemann","year":"2009","journal-title":"Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"174","DOI":"10.3109\/08820139.2014.952818","article-title":"The Measure of DAMPs and a role for S100A8 in recruiting suppressor cells in breast cancer lung metastasis","volume":"44","author":"Vrakas","year":"2015","journal-title":"Immunol. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/nri2506","article-title":"Myeloid-derived suppressor cells as regulators of the immune system","volume":"9","author":"Gabrilovich","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.coi.2010.01.021","article-title":"Myeloid-derived suppressor cell heterogeneity and subset definition","volume":"22","author":"Peranzoni","year":"2010","journal-title":"Curr. Opin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"22658","DOI":"10.1038\/srep22658","article-title":"Monocytic myeloid-derived suppressor cells from females, but not males, alleviate CVB3-induced myocarditis by increasing regulatory and CD4(+)IL-10(+) T cells","volume":"6","author":"Su","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.molimm.2017.01.013","article-title":"Expansion of CD11b(+)Ly-6C(+) myeloid-derived suppressor cells (MDSCs) driven by galectin-9 attenuates CVB3-induced myocarditis","volume":"83","author":"Zhang","year":"2017","journal-title":"Mol. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1084\/jem.20080132","article-title":"Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein","volume":"205","author":"Cheng","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s00395-012-0287-z","article-title":"The prostacyclin agonist iloprost aggravates fibrosis and enhances viral replication in enteroviral myocarditis by modulation of ERK signaling and increase of iNOS expression","volume":"107","author":"Gruhle","year":"2012","journal-title":"Basic Res. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0890-8508(91)90033-G","article-title":"Strand-specific detection of enteroviral RNA in myocardial tissue by in situ hybridization","volume":"5","author":"Hohenadl","year":"1991","journal-title":"Mol. Cell. Probes."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.celrep.2012.06.001","article-title":"Infection-induced regulation of natural killer cells by macrophages and collagen at the lymph node subcapsular sinus","volume":"2","author":"Coombes","year":"2012","journal-title":"Cell Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0928-0197(96)00217-6","article-title":"Molecular in situ localization techniques in diagnosis and pathogenicity studies of enteroviral heart disease","volume":"5","author":"Klingel","year":"1996","journal-title":"Clin. Diagn. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1056\/NEJMra0800028","article-title":"Myocarditis","volume":"360","author":"Cooper","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1073\/pnas.89.1.314","article-title":"Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: Quantitative analysis of virus replication, tissue damage, and inflammation","volume":"89","author":"Klingel","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0168-1702(99)00041-6","article-title":"Mechanisms and consequences of enterovirus persistence in cardiac myocytes and cells of the immune system","volume":"62","author":"Kandolf","year":"1999","journal-title":"Virus Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00395-019-0719-0","article-title":"Blocking the IL-1beta signalling pathway prevents chronic viral myocarditis and cardiac remodeling","volume":"114","author":"Kraft","year":"2019","journal-title":"Basic Res. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.immuni.2013.02.007","article-title":"Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation","volume":"38","author":"Kanterman","year":"2013","journal-title":"Immunity"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1158\/0008-5472.CAN-05-2429","article-title":"Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells","volume":"66","author":"Roda","year":"2006","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4852","DOI":"10.4049\/jimmunol.0803954","article-title":"Cytokine secretion is distinct from secretion of cytotoxic granules in NK cells","volume":"184","author":"Reefman","year":"2010","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.2353\/ajpath.2006.060350","article-title":"Sustained nitric oxide synthesis contributes to immunopathology in ongoing myocarditis attributable to interleukin-10 disorders","volume":"169","author":"Szalay","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8149","DOI":"10.1128\/JVI.00047-08","article-title":"Effective chemokine secretion by dendritic cells and expansion of cross-presenting CD4-\/CD8+ dendritic cells define a protective phenotype in the mouse model of coxsackievirus myocarditis","volume":"82","author":"Weinzierl","year":"2008","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1093\/eurheartj\/16.suppl_O.42","article-title":"Enterovirus-infected immune cells of spleen and lymph nodes in the murine model of chronic myocarditis: A role in pathogenesis?","volume":"16","author":"Klingel","year":"1995","journal-title":"Eur. Heart J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1161\/01.CIR.99.8.1091","article-title":"From myocarditis to cardiomyopathy: Mechanisms of inflammation and cell death: Learning from the past for the future","volume":"99","author":"Kawai","year":"1999","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Muller, I., Vogl, T., Pappritz, K., Miteva, K., Savvatis, K., Rohde, D., Most, P., Lassner, D., Pieske, B., and Kuhl, U. (2017). Pathogenic Role of the Damage-Associated Molecular Patterns S100A8 and S100A9 in Coxsackievirus B3-Induced Myocarditis. Circ. Heart Fail., 10.","DOI":"10.1161\/CIRCHEARTFAILURE.117.004125"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1002\/ehf2.12760","article-title":"Serum alarmin S100A8\/S100A9 levels and its potential role as biomarker in myocarditis","volume":"7","author":"Muller","year":"2020","journal-title":"ESC Heart Fail."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4666","DOI":"10.4049\/jimmunol.181.7.4666","article-title":"Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells","volume":"181","author":"Sinha","year":"2008","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.4049\/jimmunol.1002928","article-title":"Myeloid-derived suppressor cells infiltrate the heart in acute Trypanosoma cruzi infection","volume":"187","author":"Cuervo","year":"2011","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1016\/S0002-9440(10)64305-2","article-title":"beta2-microglobulin-associated regulation of interferon-gamma and virus-specific immunoglobulin G confer resistance against the development of chronic coxsackievirus myocarditis","volume":"162","author":"Klingel","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.1161\/01.CIR.94.11.2930","article-title":"Persistent expression of cytokine in the chronic stage of viral myocarditis in mice","volume":"94","author":"Shioi","year":"1996","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1002\/jlb.63.6.650","article-title":"Signal transduction pathways activated by the IL-1 receptor family: Ancient signaling machinery in mammals, insects, and plants","volume":"63","author":"Greene","year":"1998","journal-title":"J. Leukoc. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00395-014-0449-2","article-title":"Interleukin-6 receptor inhibition modulates the immune reaction and restores titin phosphorylation in experimental myocarditis","volume":"109","author":"Savvatis","year":"2014","journal-title":"Basic Res. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"30441","DOI":"10.18632\/oncotarget.5962","article-title":"Cutaneous bacteria induce immunosuppression","volume":"6","author":"Skabytska","year":"2015","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1126\/science.7667639","article-title":"Requirement of MIP-1 alpha for an inflammatory response to viral infection","volume":"269","author":"Cook","year":"1995","journal-title":"Science"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/889\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:59:35Z","timestamp":1760162375000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/889"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,12]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["v13050889"],"URL":"https:\/\/doi.org\/10.3390\/v13050889","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,12]]}}}