{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:34:11Z","timestamp":1760243651875,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T00:00:00Z","timestamp":1665273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"The Grant Agency of the Czech Republic (GACR)","doi-asserted-by":"publisher","award":["20-30350S"],"award-info":[{"award-number":["20-30350S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Male infertility affects approximately 14% of all European men, of which ~44% are characterized as idiopathic. There is an urgency to identify the factors that affect male fertility. One such factor, Autoimmune Regulator (AIRE), a protein found in the thymus, has been studied in the context of central tolerance functioning as a nuclear transcription modulator, responsible for the expression of tissue-restricted antigens in specialized thymic cells that prevent autoimmunity. While its expression in the testes remains enigmatic, we recently observed that sterility in mice correlates with the absence of Aire in the testes, regardless of the deficient expression in medullary thymic epithelial cells or cells of the hematopoietic system. By assessing the Aire transcript levels, we discovered that Sertoli cells are the exclusive source of Aire in the testes, where it most likely plays a non-immune role, suggesting an unknown mechanism by which testicular Aire regulates fertility. Here, we discuss these results in the context of previous reports which have suggested that infertility observed in Aire deficient mice is of an autoimmune aetiology. We present an alternative point of view for the role of Aire in testes in respect to fertility altering the perspective of how Aire\u2019s function in the testes is currently perceived.<\/jats:p>","DOI":"10.3390\/cells11193168","type":"journal-article","created":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T20:49:31Z","timestamp":1665348571000},"page":"3168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AIRE in Male Fertility: A New Hypothesis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4942-255X","authenticated-orcid":false,"given":"Jana","family":"Petrusov\u00e1","sequence":"first","affiliation":[{"name":"Laboratory of Immunobiology, Institute of Molecular Genetics of the Czech Academy of Sciences, V\u00edde\u0148sk\u00e1 1083, 142 20 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasper","family":"Manning","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Institute of Molecular Genetics of the Czech Academy of Sciences, V\u00edde\u0148sk\u00e1 1083, 142 20 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2506-9330","authenticated-orcid":false,"given":"Dominik","family":"Filipp","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Institute of Molecular Genetics of the Czech Academy of Sciences, V\u00edde\u0148sk\u00e1 1083, 142 20 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1146\/annurev.immunol.23.021704.115601","article-title":"A central role for central tolerance","volume":"24","author":"Kyewski","year":"2006","journal-title":"Annu. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"972017","DOI":"10.3389\/fcell.2022.972017","article-title":"Two complementary approaches for efficient isolation of Sertoli cells for transcriptomic analysis","volume":"10","author":"Petrusova","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/cyto.a.20129","article-title":"Flow cytometric characterization of viable meiotic and postmeiotic cells by Hoechst 33342 in mouse spermatogenesis","volume":"65","author":"Bastos","year":"2005","journal-title":"Cytom. Part A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/cyto.a.22463","article-title":"Optimized flow cytometry isolation of murine spermatocytes","volume":"85","author":"Gaysinskaya","year":"2014","journal-title":"Cytom. Part A"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/ng1297-399","article-title":"An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains","volume":"17","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ng1297-393","article-title":"Positional cloning of the APECED gene","volume":"17","author":"Nagamine","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/hmg\/7.10.1547","article-title":"Gene defect behind APECED: A new clue to autoimmunity","volume":"7","author":"Bjorses","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1126\/science.1075958","article-title":"Projection of an immunological self shadow within the thymus by the aire protein","volume":"298","author":"Anderson","year":"2002","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1093\/hmg\/11.4.397","article-title":"Aire deficient mice develop multiple features of APECED phenotype and show altered immune response","volume":"11","author":"Ramsey","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1146\/annurev.immunol.25.022106.141532","article-title":"Aire","volume":"27","author":"Mathis","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nri3667","article-title":"Positive and negative selection of the T cell repertoire: What thymocytes see (and don\u2019t see)","volume":"14","author":"Klein","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/imr.12419","article-title":"Autoimmune regulator and self-tolerance-molecular and clinical aspects","volume":"271","author":"Abramson","year":"2016","journal-title":"Immunol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/ni.3675","article-title":"The transcriptional regulator Aire binds to and activates super-enhancers","volume":"18","author":"Bansal","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cell.2009.12.030","article-title":"Aire\u2019s partners in the molecular control of immunological tolerance","volume":"140","author":"Abramson","year":"2010","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/s13059-016-1079-9","article-title":"Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells","volume":"17","author":"Guyon","year":"2016","journal-title":"Genome Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1101\/gr.171645.113","article-title":"Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia","volume":"24","author":"Sansom","year":"2014","journal-title":"Genome Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/ni.3246","article-title":"Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells","volume":"16","author":"Brennecke","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/ni.3247","article-title":"Aire controls gene expression in the thymic epithelium with ordered stochasticity","volume":"16","author":"Meredith","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1056\/NEJMra1713301","article-title":"Autoimmune polyendocrine syndromes","volume":"378","author":"Husebye","year":"2018","journal-title":"New Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1006\/bbrc.1999.0308","article-title":"Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla","volume":"257","author":"Heino","year":"1999","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1177\/002215540104900207","article-title":"Subcellular location and expression pattern of autoimmune regulator (Aire), the mouse orthologue for human gene defective in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED)","volume":"49","author":"Halonen","year":"2001","journal-title":"J. Histochem. Cytochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/path.1493","article-title":"A comparative study of mRNA and protein expression of the autoimmune regulator gene (Aire) in embryonic and adult murine tissues","volume":"202","author":"Adamson","year":"2004","journal-title":"J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1126\/science.1159407","article-title":"Deletional tolerance mediated by extrathymic Aire-expressing cells","volume":"321","author":"Gardner","year":"2008","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.immuni.2013.08.005","article-title":"Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4(+) T cells","volume":"39","author":"Gardner","year":"2013","journal-title":"Immunity"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1084\/jem.20181430","article-title":"Aire-expressing ILC3-like cells in the lymph node display potent APC features","volume":"216","author":"Yamano","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1038\/s41590-022-01247-6","article-title":"Extrathymic expression of Aire controls the induction of effective TH17 cell-mediated immune response to Candida albicans","volume":"23","author":"Dobes","year":"2022","journal-title":"Nat. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.4049\/jimmunol.180.3.1338","article-title":"Expression of Aire and the early wave of apoptosis in spermatogenesis","volume":"180","author":"Schaller","year":"2008","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1074\/mcp.M115.052951","article-title":"Autoimmune regulator (AIRE) is expressed in spermatogenic cells, and it altered the expression of several nucleic-acid-binding and cytoskeletal proteins in Germ cell 1 spermatogonial (GC1-spg) cells","volume":"15","author":"Radhakrishnan","year":"2016","journal-title":"Mol. Cell Proteomics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/sji.12280","article-title":"Autoimmunity, not a developmental defect, is the cause for subfertility of Autoimmune regulator (Aire) deficient mice","volume":"81","author":"Kekalainen","year":"2015","journal-title":"Scand. J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1016\/j.ajpath.2021.05.021","article-title":"Multiple lesions contribute to infertility in males lacking autoimmune regulator","volume":"191","author":"Warren","year":"2021","journal-title":"Am. J. Pathol."},{"key":"ref_31","first-page":"2031","article-title":"An aberrant prostate antigen-specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans","volume":"119","author":"Hou","year":"2009","journal-title":"J. Clin. Invest."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1093\/humrep\/dei073","article-title":"Reduced semen quality in chronic prostatitis patients that have cellular autoimmune response to prostate antigens","volume":"20","author":"Motrich","year":"2005","journal-title":"Hum. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"641164","DOI":"10.3389\/fimmu.2021.641164","article-title":"The role of AIRE deficiency in infertility and its potential pathogenesis","volume":"12","author":"Zou","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13009","DOI":"10.1073\/pnas.0806874105","article-title":"B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients","volume":"105","author":"Gavanescu","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/eji.201747267","article-title":"A novel conditional Aire allele enables cell-specific ablation of the immune tolerance regulator Aire","volume":"48","author":"Dobes","year":"2018","journal-title":"Eur. J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12258","DOI":"10.1073\/pnas.91.25.12258","article-title":"Isolation of a DEAD-family protein gene that encodes a murine homolog of Drosophila vasa and its specific expression in germ cell lineage","volume":"91","author":"Fujiwara","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1101\/gad.14.7.841","article-title":"The mouse homolog of Drosophila Vasa is required for the development of male germ cells","volume":"14","author":"Tanaka","year":"2000","journal-title":"Genes Dev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6984","DOI":"10.1128\/MCB.21.20.6984-6998.2001","article-title":"Novel meiosis-specific isoform of mammalian SMC1","volume":"21","author":"Revenkova","year":"2001","journal-title":"Mol. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Petrusova, J., Havalda, R., Flachs, P., Venit, T., Darasova, A., Hulkova, L., Sztacho, M., and Hozak, P. (2022). Focal adhesion protein Vinculin is required for proper meiotic progression during mouse spermatogenesis. Cells, 11.","DOI":"10.3390\/cells11132013"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1089\/cell.2013.0008","article-title":"An improved protocol for isolation and culturing of mouse spermatogonial stem cells","volume":"15","author":"Baazm","year":"2013","journal-title":"Cell Reprogram"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S1097-2765(00)80404-9","article-title":"The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility","volume":"5","author":"Yuan","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1016\/j.febslet.2014.07.024","article-title":"The transcription factors Sox5 and Sox9 regulate Catsper1 gene expression","volume":"588","author":"Guarneros","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"708","DOI":"10.4103\/1008-682X.156119","article-title":"Phosphorylation of Izumo1 and Its Role in Male Infertility","volume":"17","author":"Young","year":"2015","journal-title":"Asian J. Androl."},{"key":"ref_44","first-page":"44","article-title":"Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression","volume":"144","author":"Chen","year":"2017","journal-title":"Development"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Grive, K.J., Hu, Y., Shu, E., Grimson, A., Elemento, O., Grenier, J.K., and Cohen, P.E. (2019). Dynamic transcriptome profiles within spermatogonial and spermatocyte populations during postnatal testis maturation revealed by single-cell sequencing. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1007810"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.celrep.2018.10.026","article-title":"The mammalian spermatogenesis single-cell transcriptome, from spermatogonial stem cells to spermatids","volume":"25","author":"Hermann","year":"2018","journal-title":"Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1089\/10665270050081478","article-title":"A greedy algorithm for aligning DNA sequences","volume":"7","author":"Zhang","year":"2000","journal-title":"J. Comput. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1210\/me.2014-1356","article-title":"Research resource: The dynamic transcriptional profile of sertoli cells during the progression of spermatogenesis","volume":"29","author":"Zimmermann","year":"2015","journal-title":"Mol. Endocrinol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Skinner, M.K. (2018). Male Reproduction. Encyclopedia of Reproduction, Academic Press. [2nd ed.].","DOI":"10.1016\/B978-0-12-801238-3.64554-3"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s12064-019-00306-1","article-title":"When few survive to tell the tale: Thymus and gonad as auditioning organs: Historical overview","volume":"139","author":"Forsdyke","year":"2020","journal-title":"Theory Biosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"701","DOI":"10.2174\/0929867323666160112122724","article-title":"Effective delivery of male contraceptives behind the blood-testis barrier (BTB)-lesson from adjudin","volume":"23","author":"Chen","year":"2016","journal-title":"Curr. Med. Chem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/3168\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:48:53Z","timestamp":1760143733000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/3168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,9]]},"references-count":51,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["cells11193168"],"URL":"https:\/\/doi.org\/10.3390\/cells11193168","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2022,10,9]]}}}