AIRE in Male Fertility: A New Hypothesis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Breeding Experiment
2.2. Testes Collection and Statistical Analysis
2.3. Collection of Cells from Seminiferous Tubule
2.4. Isolation of RNA and qRT–PCR
2.5. Immunofluorescence and Microscopy
3. Results
3.1. Thymic Aire as an Essential Mediator of Central Immune Tolerance
3.2. Extrathymic Aire Expression
3.3. Aire in Testes and Male Sterility
3.4. Which Cells in Seminiferous Tubule Express Aire?
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Kyewski, B.; Klein, L. A central role for central tolerance. Annu. Rev. Immunol. 2006, 24, 571–606. [Google Scholar] [CrossRef] [PubMed]
- Petrusova, J.; Manning, J.; Kubovčiak, J.; Kolář, M.; Filipp, D. Two complementary approaches for efficient isolation of Sertoli cells for transcriptomic analysis. Front. Cell Dev. Biol. 2022, 10, 972017. [Google Scholar] [CrossRef] [PubMed]
- Bastos, H.; Lassalle, B.; Chicheportiche, A.; Riou, L.; Testart, J.; Allemand, I.; Fouchet, P. Flow cytometric characterization of viable meiotic and postmeiotic cells by Hoechst 33342 in mouse spermatogenesis. Cytom. Part A 2005, 65, 40–49. [Google Scholar] [CrossRef]
- Gaysinskaya, V.; Soh, I.Y.; van der Heijden, G.W.; Bortvin, A. Optimized flow cytometry isolation of murine spermatocytes. Cytom. Part A 2014, 85, 556–565. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Finnish-German, A.C. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 1997, 17, 399–403. [Google Scholar] [CrossRef]
- Nagamine, K.; Peterson, P.; Scott, H.S.; Kudoh, J.; Minoshima, S.; Heino, M.; Krohn, K.J.; Lalioti, M.D.; Mullis, P.E.; Antonarakis, S.E.; et al. Positional cloning of the APECED gene. Nat. Genet. 1997, 17, 393–398. [Google Scholar] [CrossRef]
- Bjorses, P.; Aaltonen, J.; Horelli-Kuitunen, N.; Yaspo, M.L.; Peltonen, L. Gene defect behind APECED: A new clue to autoimmunity. Hum. Mol. Genet. 1998, 7, 1547–1553. [Google Scholar] [CrossRef] [Green Version]
- Anderson, M.S.; Venanzi, E.S.; Klein, L.; Chen, Z.; Berzins, S.P.; Turley, S.J.; von Boehmer, H.; Bronson, R.; Dierich, A.; Benoist, C.; et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002, 298, 1395–1401. [Google Scholar] [CrossRef] [Green Version]
- Ramsey, C.; Winqvist, O.; Puhakka, L.; Halonen, M.; Moro, A.; Kampe, O.; Eskelin, P.; Pelto-Huikko, M.; Peltonen, L. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 2002, 11, 397–409. [Google Scholar] [CrossRef]
- Mathis, D.; Benoist, C. Aire. Annu. Rev. Immunol. 2009, 27, 287–312. [Google Scholar] [CrossRef]
- Klein, L.; Kyewski, B.; Allen, P.M.; Hogquist, K.A. Positive and negative selection of the T cell repertoire: What thymocytes see (and don’t see). Nat. Rev. Immunol. 2014, 14, 377–391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abramson, J.; Husebye, E.S. Autoimmune regulator and self-tolerance-molecular and clinical aspects. Immunol. Rev. 2016, 271, 127–140. [Google Scholar] [CrossRef] [PubMed]
- Bansal, K.; Yoshida, H.; Benoist, C.; Mathis, D. The transcriptional regulator Aire binds to and activates super-enhancers. Nat. Immunol. 2017, 18, 263–273. [Google Scholar] [CrossRef] [PubMed]
- Abramson, J.; Giraud, M.; Benoist, C.; Mathis, D. Aire’s partners in the molecular control of immunological tolerance. Cell 2010, 140, 123–135. [Google Scholar] [CrossRef] [Green Version]
- Danan-Gotthold, M.; Guyon, C.; Giraud, M.; Levanon, E.Y.; Abramson, J. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol. 2016, 17, 219. [Google Scholar] [CrossRef] [Green Version]
- Sansom, S.N.; Shikama-Dorn, N.; Zhanybekova, S.; Nusspaumer, G.; Macaulay, I.C.; Deadman, M.E.; Heger, A.; Ponting, C.P.; Hollander, G.A. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res. 2014, 24, 1918–1931. [Google Scholar] [CrossRef] [Green Version]
- Brennecke, P.; Reyes, A.; Pinto, S.; Rattay, K.; Nguyen, M.; Kuchler, R.; Huber, W.; Kyewski, B.; Steinmetz, L.M. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat. Immunol. 2015, 16, 933–941. [Google Scholar] [CrossRef] [Green Version]
- Meredith, M.; Zemmour, D.; Mathis, D.; Benoist, C. Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat. Immunol. 2015, 16, 942–949. [Google Scholar] [CrossRef] [Green Version]
- Husebye, E.S.; Anderson, M.S.; Kampe, O. Autoimmune polyendocrine syndromes. New Engl. J. Med. 2018, 378, 1132–1141. [Google Scholar] [CrossRef]
- Heino, M.; Peterson, P.; Kudoh, J.; Nagamine, K.; Lagerstedt, A.; Ovod, V.; Ranki, A.; Rantala, I.; Nieminen, M.; Tuukkanen, J.; et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem. Biophys. Res. Commun 1999, 257, 821–825. [Google Scholar] [CrossRef]
- Halonen, M.; Pelto-Huikko, M.; Eskelin, P.; Peltonen, L.; Ulmanen, I.; Kolmer, M. Subcellular location and expression pattern of autoimmune regulator (Aire), the mouse orthologue for human gene defective in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). J. Histochem. Cytochem. 2001, 49, 197–208. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Adamson, K.A.; Pearce, S.H.; Lamb, J.R.; Seckl, J.R.; Howie, S.E. A comparative study of mRNA and protein expression of the autoimmune regulator gene (Aire) in embryonic and adult murine tissues. J. Pathol. 2004, 202, 180–187. [Google Scholar] [CrossRef]
- Gardner, J.M.; Devoss, J.J.; Friedman, R.S.; Wong, D.J.; Tan, Y.X.; Zhou, X.; Johannes, K.P.; Su, M.A.; Chang, H.Y.; Krummel, M.F.; et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 2008, 321, 843–847. [Google Scholar] [CrossRef] [Green Version]
- Gardner, J.M.; Metzger, T.C.; McMahon, E.J.; Au-Yeung, B.B.; Krawisz, A.K.; Lu, W.; Price, J.D.; Johannes, K.P.; Satpathy, A.T.; Murphy, K.M.; et al. Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4(+) T cells. Immunity 2013, 39, 560–572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yamano, T.; Dobes, J.; Voboril, M.; Steinert, M.; Brabec, T.; Zietara, N.; Dobesova, M.; Ohnmacht, C.; Laan, M.; Peterson, P.; et al. Aire-expressing ILC3-like cells in the lymph node display potent APC features. J. Exp. Med. 2019, 216, 1027–1037. [Google Scholar] [CrossRef] [Green Version]
- Dobes, J.; Ben-Nun, O.; Binyamin, A.; Stoler-Barak, L.; Oftedal, B.E.; Goldfarb, Y.; Kadouri, N.; Gruper, Y.; Givony, T.; Zalayat, I.; et al. Extrathymic expression of Aire controls the induction of effective TH17 cell-mediated immune response to Candida albicans. Nat. Immunol. 2022, 23, 1098–1108. [Google Scholar] [CrossRef] [PubMed]
- Schaller, C.E.; Wang, C.L.; Beck-Engeser, G.; Goss, L.; Scott, H.S.; Anderson, M.S.; Wabl, M. Expression of Aire and the early wave of apoptosis in spermatogenesis. J. Immunol. 2008, 180, 1338–1343. [Google Scholar] [CrossRef] [Green Version]
- Radhakrishnan, K.; Bhagya, K.P.; Kumar, A.T.; Devi, A.N.; Sengottaiyan, J.; Kumar, P.G. 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. Mol. Cell Proteomics 2016, 15, 2686–2698. [Google Scholar] [CrossRef] [Green Version]
- Kekalainen, E.; Pontynen, N.; Meri, S.; Arstila, T.P.; Jarva, H. Autoimmunity, not a developmental defect, is the cause for subfertility of Autoimmune regulator (Aire) deficient mice. Scand. J. Immunol. 2015, 81, 298–304. [Google Scholar] [CrossRef]
- Warren, B.D.; Ahn, S.H.; Brittain, K.S.; Nanjappa, M.K.; Wang, H.; Wang, J.; Blanco, G.; Sanchez, G.; Fan, Y.; Petroff, B.K.; et al. Multiple lesions contribute to infertility in males lacking autoimmune regulator. Am. J. Pathol. 2021, 191, 1592–1609. [Google Scholar] [CrossRef]
- Hou, Y.; DeVoss, J.; Dao, V.; Kwek, S.; Simko, J.P.; McNeel, D.G.; Anderson, M.S.; Fong, L. An aberrant prostate antigen-specific immune response causes prostatitis in mice and is associated with chronic prostatitis in humans. J. Clin. Invest. 2009, 119, 2031–2041. [Google Scholar] [CrossRef] [PubMed]
- Motrich, R.D.; Maccioni, M.; Molina, R.; Tissera, A.; Olmedo, J.; Riera, C.M.; Rivero, V.E. Reduced semen quality in chronic prostatitis patients that have cellular autoimmune response to prostate antigens. Hum. Reprod. 2005, 20, 2567–2572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zou, X.; Zhang, Y.; Wang, X.; Zhang, R.; Yang, W. The role of AIRE deficiency in infertility and its potential pathogenesis. Front. Immunol. 2021, 12, 641164. [Google Scholar] [CrossRef] [PubMed]
- Gavanescu, I.; Benoist, C.; Mathis, D. B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients. Proc. Natl. Acad. Sci. USA 2008, 105, 13009–13014. [Google Scholar] [CrossRef] [Green Version]
- Dobes, J.; Edenhofer, F.; Voboril, M.; Brabec, T.; Dobesova, M.; Cepkova, A.; Klein, L.; Rajewsky, K.; Filipp, D. A novel conditional Aire allele enables cell-specific ablation of the immune tolerance regulator Aire. Eur. J. Immunol. 2018, 48, 546–548. [Google Scholar] [CrossRef] [Green Version]
- Fujiwara, Y.; Komiya, T.; Kawabata, H.; Sato, M.; Fujimoto, H.; Furusawa, M.; Noce, T. Isolation of a DEAD-family protein gene that encodes a murine homolog of Drosophila vasa and its specific expression in germ cell lineage. Proc. Natl. Acad. Sci. USA 1994, 91, 12258–12262. [Google Scholar] [CrossRef] [Green Version]
- Tanaka, S.S.; Toyooka, Y.; Akasu, R.; Katoh-Fukui, Y.; Nakahara, Y.; Suzuki, R.; Yokoyama, M.; Noce, T. The mouse homolog of Drosophila Vasa is required for the development of male germ cells. Genes Dev. 2000, 14, 841–853. [Google Scholar] [CrossRef]
- Revenkova, E.; Eijpe, M.; Heyting, C.; Gross, B.; Jessberger, R. Novel meiosis-specific isoform of mammalian SMC1. Mol. Cell Biol. 2001, 21, 6984–6998. [Google Scholar] [CrossRef] [Green Version]
- Petrusova, J.; Havalda, R.; Flachs, P.; Venit, T.; Darasova, A.; Hulkova, L.; Sztacho, M.; Hozak, P. Focal adhesion protein Vinculin is required for proper meiotic progression during mouse spermatogenesis. Cells 2022, 11, 2013. [Google Scholar] [CrossRef]
- Baazm, M.; Abolhassani, F.; Abbasi, M.; Habibi Roudkenar, M.; Amidi, F.; Beyer, C. An improved protocol for isolation and culturing of mouse spermatogonial stem cells. Cell Reprogram 2013, 15, 329–336. [Google Scholar] [CrossRef]
- Yuan, L.; Liu, J.G.; Zhao, J.; Brundell, E.; Daneholt, B.; Hoog, C. The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol. Cell 2000, 5, 73–83. [Google Scholar] [CrossRef]
- Mata-Rocha, M.; Hernandez-Sanchez, J.; Guarneros, G.; de la Chesnaye, E.; Sanchez-Tusie, A.A.; Trevino, C.L.; Felix, R.; Oviedo, N. The transcription factors Sox5 and Sox9 regulate Catsper1 gene expression. FEBS Lett. 2014, 588, 3352–3360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Young, S.A.; Aitken, J.; Baker, M.A. Phosphorylation of Izumo1 and Its Role in Male Infertility. Asian J. Androl. 2015, 17, 708–710. [Google Scholar] [CrossRef] [PubMed]
- Chen, M.; Zhang, L.; Cui, X.; Lin, X.; Li, Y.; Wang, Y.; Wang, Y.; Qin, Y.; Chen, D.; Han, C.; et al. Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression. Development 2017, 144, 44–53. [Google Scholar] [CrossRef] [Green Version]
- Grive, K.J.; Hu, Y.; Shu, E.; Grimson, A.; Elemento, O.; Grenier, J.K.; Cohen, P.E. Dynamic transcriptome profiles within spermatogonial and spermatocyte populations during postnatal testis maturation revealed by single-cell sequencing. PLoS Genet. 2019, 15, e1007810. [Google Scholar] [CrossRef] [Green Version]
- Hermann, B.P.; Cheng, K.; Singh, A.; Roa-De La Cruz, L.; Mutoji, K.N.; Chen, I.C.; Gildersleeve, H.; Lehle, J.D.; Mayo, M.; Westernstroer, B.; et al. The mammalian spermatogenesis single-cell transcriptome, from spermatogonial stem cells to spermatids. Cell Rep. 2018, 25, 1650–1667 e1658. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Z.; Schwartz, S.; Wagner, L.; Miller, W. A greedy algorithm for aligning DNA sequences. J. Comput. Biol. 2000, 7, 203–214. [Google Scholar] [CrossRef]
- Zimmermann, C.; Stevant, I.; Borel, C.; Conne, B.; Pitetti, J.L.; Calvel, P.; Kaessmann, H.; Jegou, B.; Chalmel, F.; Nef, S. Research resource: The dynamic transcriptional profile of sertoli cells during the progression of spermatogenesis. Mol. Endocrinol. 2015, 29, 627–642. [Google Scholar] [CrossRef] [Green Version]
- Jégou, B.; Skinner, M.K. Male Reproduction. In Encyclopedia of Reproduction, 2nd ed.; Skinner, M.K., Ed.; Academic Press: Oxford, 2018; ISBN 9780128118993. [Google Scholar]
- Forsdyke, D.R. When few survive to tell the tale: Thymus and gonad as auditioning organs: Historical overview. Theory Biosci. 2020, 139, 95–104. [Google Scholar] [CrossRef] [Green Version]
- Chen, H.; Mruk, D.D.; Xia, W.; Bonanomi, M.; Silvestrini, B.; Cheng, C.Y. Effective delivery of male contraceptives behind the blood-testis barrier (BTB)-lesson from adjudin. Curr. Med. Chem. 2016, 23, 701–713. [Google Scholar] [CrossRef]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Petrusová, J.; Manning, J.; Filipp, D. AIRE in Male Fertility: A New Hypothesis. Cells 2022, 11, 3168. https://doi.org/10.3390/cells11193168
Petrusová J, Manning J, Filipp D. AIRE in Male Fertility: A New Hypothesis. Cells. 2022; 11(19):3168. https://doi.org/10.3390/cells11193168
Chicago/Turabian StylePetrusová, Jana, Jasper Manning, and Dominik Filipp. 2022. "AIRE in Male Fertility: A New Hypothesis" Cells 11, no. 19: 3168. https://doi.org/10.3390/cells11193168