{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:08:31Z","timestamp":1791144511981,"version":"4.1.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004955","name":"\u00d6sterreichische Forschungsf\u00f6rderungsgesellschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Natural killer (NK) cells play an important role in recognizing and killing pathogen-infected or malignant cells. Changes in their numbers or activation can contribute to several diseases and pathologies including systemic sclerosis (SSc), an autoimmune disease characterized by inflammation and tissue remodeling. In these patients, increased expression of the AP-1 transcription factor, Fra-2 was reported. In mice ectopic overexpression of Fra-2 (TG) leads to SSc with strong pulmonary fibrosis, pulmonary hypertension, and inflammation. Analysis of the underlying immune cell profile in the lungs of young TG mice, which do not yet show any signs of lung disease, revealed increased numbers of eosinophils and T cells but strongly reduced NK numbers. Therefore, we aimed to identify the cause of the absence of NK cells in the lungs of these mice and to determine the potential role of Fra-2 in NK development. Examination of inflammatory cell distribution in TG mice revealed similar NK deficiencies in the spleen, blood, and bone marrow. Deeper analysis of the WT and TG bone marrow revealed a potential NK cell developmental defect beginning at the preNKP stage. To determine whether this defect was cell-intrinsic or extrinsic, mixed bone marrow chimera and <jats:italic>in vitro<\/jats:italic> differentiation experiments were performed. Both experiments showed that the defect caused by Fra-2 was primarily cell-intrinsic and minimally dependent on the environment. Closer examination of surface markers and transcription factors required for NK development, revealed the expected receptor distribution but changes in transcription factor expression. We found a significant reduction in Nfil3, which is essential for the transition of common lymphoid cells to NK committed precursor cells and an AP-1 binding site in the promotor of this gene. In Summary, our data demonstrates that regulation of Fra-2 is essential for NK development and maturation, and suggests that the early NK dysfunction plays an important role in the pathogenesis of systemic sclerosis.<\/jats:p>","DOI":"10.3389\/fimmu.2022.909270","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T07:17:48Z","timestamp":1655882268000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Fra-2 Is a Dominant Negative Regulator of Natural Killer Cell Development"],"prefix":"10.3389","volume":"13","author":[{"given":"Diana","family":"Schnoegl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Hochgerner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Gotthardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh M.","family":"Marsh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01869","article-title":"Natural Killer Cells: Development, Maturation, and Clinical Utilization","volume":"9","author":"Abel","year":"2018","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.110619\/-\/DC1","article-title":"Impaired Natural Killer Cell Phenotype and Function in Idiopathic and Heritable Pulmonary Arterial Hypertension","volume":"126","author":"Ormiston","year":"2012","journal-title":"Circulation"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2005.23767","article-title":"Abnormal Natural Killer Cell Function in Systemic Sclerosis: Altered Cytokine Production and Defective Killing Activity","volume":"125","author":"Horikawa","year":"2005","journal-title":"J Invest Dermatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/J.1365-2567.2009.03167.X","article-title":"Natural Killer Cells in Infection and Inflammation of the Lung","volume":"128","author":"Culley","year":"2009","journal-title":"Immunology"},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.1016\/B978-0-12-374279-7.04002-9","article-title":"Development of Natural Killer Cells and ILC1","volume-title":"Encyclopedia of Immunobiology","author":"Kee","year":"2016"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-04-348912","article-title":"Identification of the Earliest Natural Killer Cell \u2013 Committed Progenitor in Murine Bone Marrow","volume":"118","author":"Fathman","year":"2011","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-11-318956","article-title":"Brief Report Identification of the Earliest NK-Cell Precursor in the Mouse BM","volume":"117","author":"Carotta","year":"2011","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2016.01.007","article-title":"Development and Maturation of Natural Killer Cells","volume":"39","author":"Geiger","year":"2017","journal-title":"Curr Opin Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/GENE.2014.55","article-title":"NK Cell Development in Bone Marrow and Liver: Site Matters","volume":"15","author":"Gotthardt","year":"2014","journal-title":"Genes Immun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1787","article-title":"The Basic Leucine Zipper Transcription Factor E4BP4 Is Essential for Natural Killer Cell Development","volume":"10","author":"Gascoyne","year":"2009","journal-title":"Nat Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.jbior.2016.05.001","article-title":"Gene Regulation in the Immediate-Early Response Process","volume":"62","author":"Bahrami","year":"2016","journal-title":"Adv Biol Regul"},{"key":"B12","doi-asserted-by":"publisher","first-page":"109408","DOI":"10.1016\/j.cellsig.2019.109408","article-title":"Transcription Factor Fra-2 and Its Emerging Role in Matrix Deposition, Proliferation and Inflammation in Chronic Lung Diseases","volume":"64","author":"Birnhuber","year":"2019","journal-title":"Cell Signal"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI125366","article-title":"Fra-2-Expressing Macrophages Promote Lung Fibrosis in Mice","volume":"129","author":"Ucero","year":"2019","journal-title":"J Clin Invest"},{"key":"B14","doi-asserted-by":"publisher","first-page":"107826","DOI":"10.1016\/j.celrep.2020.107826","article-title":"The AP1 Transcription Factor Fosl2 Promotes Systemic Autoimmunity and Inflammation by Repressing Treg Development","volume":"31","author":"Renoux","year":"2020","journal-title":"Cell Rep"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1084\/JEM.20160514","article-title":"Fra-2 Regulates B Cell Development by Enhancing IRF4 and Foxo1 Transcription","volume":"214","author":"Ubieta","year":"2017","journal-title":"J Exp Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1074\/JBC.M207414200","article-title":"Specific Activation of Human Interleukin-5 Depends on De Novo Synthesis of an AP-1 Complex","volume":"277","author":"Schwenger","year":"2002","journal-title":"J Biol Chem"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.0803577","article-title":"Aberrant Selection and Function of Invariant NKT Cells in the Absence of AP-1 Transcription Factor Fra-2","volume":"183","author":"Lawson","year":"2009","journal-title":"J Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1900154","DOI":"10.1183\/13993003.00154-2019","article-title":"IL-1 Receptor Blockade Skews Inflammation Towards Th2 in a Mouse Model of Systemic Sclerosis","volume":"54","author":"Birnhuber","year":"2019","journal-title":"Eur Respir J"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801414105","article-title":"Development of Pulmonary Fibrosis Through a Pathway Involving the Transcription Factor Fra-2\/AP-1","volume":"105","author":"Eferl","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101819","article-title":"Machine Learning Analysis of the Bleomycin Mouse Model Reveals the Compartmental and Temporal Inflammatory Pulmonary Fingerprint","volume":"23","author":"Bordag","year":"2020","journal-title":"iScience"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2018.02018\/BIBTEX","article-title":"Fra2 Overexpression in Mice Leads to non-Allergic Asthma Development in an IL-13 Dependent Manner","volume":"9","author":"Gungl","year":"2018","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1002\/path.4303","article-title":"Meprin\u03b2, a Novel Mediator of Vascular Remodelling Underlying Pulmonary Hypertension","volume":"233","author":"Biasin","year":"2014","journal-title":"J Pathol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1152\/AJPLUNG.00505.2020","article-title":"Pulmonary Fibrosis in Fra-2 Transgenic Mice Is Associated With Decreased Numbers of Alveolar Macrophages and Increased Susceptibility to Pneumococcal Pneumonia","volume":"320","author":"Tabeling","year":"2021","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1111\/J.1600-065X.2007.00563.X","article-title":"The Trafficking of Natural Killer Cells","volume":"220","author":"Gr\u00e9goire","year":"2007","journal-title":"Immunol Rev"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.1.409","article-title":"Regulation of Human DAP10 Gene Expression in NK and T Cells by Ap-1 Transcription Factors","volume":"180","author":"Marusina","year":"2008","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1093\/INTIMM\/DXT038","article-title":"The AP-1 Transcription Factor JunD Activates the Leukocyte Immunoglobulin-Like Receptor 1 Distal Promoter","volume":"26","author":"Davidson","year":"2014","journal-title":"Int Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02347-2021","article-title":"Pirfenidone Exacerbates Th2-Driven Vasculopathy in a Mouse Model of SSc-ILD","volume":"2102347","author":"Birnhuber","year":"2022","journal-title":"Eur Respir J"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/S00109-019-01783-Z","article-title":"Bone Marrow Chimeras\u2014A Vital Tool in Basic and Translational Research","volume":"97","author":"Ferreira","year":"2019","journal-title":"J Mol Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00477.2017","article-title":"Spontaneous Pulmonary Hypertension in Genetic Mouse Models of Natural Killer Cell Deficiency","volume":"315","author":"Matthew R\u00e4tsep","year":"2018","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20140145","article-title":"Nfil3 is Required for the Development of All Innate Lymphoid Cell Subsets","volume":"211","author":"Seillet","year":"2014","journal-title":"J Exp Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.it.2013.07.005","article-title":"Location and Cellular Stages of NK Cell Development","volume":"34","author":"Yu","year":"2014","journal-title":"Trends Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1182\/BLOOD-2008-10-187179","article-title":"Maturation of Mouse NK Cells is a 4-Stage Developmental Program","volume":"113","author":"Chiossone","year":"2009","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2981","DOI":"10.1084\/JEM.20130417","article-title":"Nfil3-Independent Lineage Maintenance and Antiviral Response of Natural Killer Cells","volume":"210","author":"Firth","year":"2013","journal-title":"J Exp Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700981","article-title":"Multiple Levels of Control Determine How E4bp4\/Nfil3 Regulates NK Cell Development","volume":"200","author":"Kostrzewski","year":"2018","journal-title":"J Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.02.057","article-title":"NFIL3 Orchestrates the Emergence of Common Helper Innate Lymphoid Cell Precursors","volume":"10","author":"Xu","year":"2015","journal-title":"Cell Rep"},{"key":"B36","doi-asserted-by":"publisher","first-page":"14677","DOI":"10.1038\/ncomms14677","article-title":"Smad3 Promotes Cancer Progression by Inhibiting E4BP4-Mediated NK Cell Development","volume":"8","author":"Tang","year":"2017","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2019.02590\/BIBTEX","article-title":"JAK\/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation","volume":"10","author":"Gotthardt","year":"2019","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-0732","article-title":"STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch From Tumor Surveillance to Tumor Promotion","volume":"6","author":"Gotthardt","year":"2016","journal-title":"Cancer Discov"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e90370","DOI":"10.1371\/journal.pone.0090370","article-title":"FRA2 Is a STAT5 Target Gene Regulated by IL-2 in Human CD4 T Cells","volume":"9","author":"Rani","year":"2014","journal-title":"PLoS ONE"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-021-00742-6","article-title":"Release of Notch Activity Coordinated by IL-1\u03b2 Signalling Confers Differentiation Plasticity of Airway Progenitors via Fosl2 During Alveolar Regeneration","volume":"23","author":"Choi","year":"2021","journal-title":"Nat Cell Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.909270\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T07:17:55Z","timestamp":1655882275000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.909270\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2022.909270"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.909270","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]},"article-number":"909270"}}