{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:46:40Z","timestamp":1790434000036,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["MA1080\/27-1 and 31-1 (project number 456828204) and SFB1123 TP Z02"],"award-info":[{"award-number":["MA1080\/27-1 and 31-1 (project number 456828204) and SFB1123 TP Z02"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cation channel TRPV2 is known to be expressed by murine macrophages and is crucially involved in their functionality. Macrophages are frequent cells of the mouse testis, an immune-privileged and steroid-producing organ. TRPV2 expression by testicular macrophages and possible changes associated with age or inflammation have not been investigated yet. Therefore, we studied testes of young adult and old wild-type (WT) and AROM+ mice, i.e., transgenic mice overexpressing aromatase. In these animals, inflammatory changes are described in the testis, involving active macrophages, which increase with age. This is associated with impaired spermatogenesis and therefore AROM+ mice are a model for male infertility associated with sterile inflammation. In WT animals, testicular TRPV2 expression was mapped to interstitial CD206+ and peritubular MHC II+ macrophages, with higher levels in CD206+ cells. Expression levels of TRPV2 and most macrophage markers did not increase significantly in old mice, with the exception of CD206. As the number of TRPV2+ testicular macrophages was relatively small, their possible involvement in testicular functions and in aging in WT mice remains to be further studied. In AROM+ testis, TRPV2 was readily detected and levels increased significantly with age, together with macrophage markers and TNF-\u03b1. TRPV2 co-localized with F4\/80 in macrophages and further studies showed that TRPV2 is mainly expressed by unusual CD206+MHC II+ macrophages, arising in the testis of these animals. Rescue experiments (aromatase inhibitor treatment and crossing with ER\u03b1KO mice) restored the testicular phenotype and also abolished the elevated expression of TRPV2, macrophage and inflammation markers. This suggests that TRPV2+ macrophages of the testis are part of an inflammatory cascade initiated by an altered sex hormone balance in AROM+ mice. The changes in testis are distinct from the described alterations in other organs of AROM+, such as prostate and spleen. When we monitored TRPV2 levels in another immune-privileged organ, namely the brain, we found that levels of TRPV2 were not elevated in AROM+ and remained stable during aging. In the adrenal, which similar to the testis produces steroids, we found slight, albeit not significant increases in TRPV2 in both AROM+ and WT mice, which were associated with age. Thus, the changes in the testis are specific for this organ.<\/jats:p>","DOI":"10.3390\/ijms22094727","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T10:30:41Z","timestamp":1619692241000},"page":"4727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Exploring the Ion Channel TRPV2 and Testicular Macrophages in Mouse Testis"],"prefix":"10.3390","volume":"22","author":[{"given":"Katja","family":"Eubler","sequence":"first","affiliation":[{"name":"Cell Biology-Anatomy III, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig-Maximilian-University (LMU), D-82152 Planegg-Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Rantakari","sequence":"additional","affiliation":[{"name":"Turku Bioscience Center, University of Turku and \u00c5bo Akademi University, FI-20300 Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Gerke","sequence":"additional","affiliation":[{"name":"Turku Bioscience Center, University of Turku and \u00c5bo Akademi University, FI-20300 Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Cell Biology-Anatomy III, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig-Maximilian-University (LMU), D-82152 Planegg-Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Missel","sequence":"additional","affiliation":[{"name":"Cell Biology-Anatomy III, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig-Maximilian-University (LMU), D-82152 Planegg-Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Schmid","sequence":"additional","affiliation":[{"name":"Cell Biology-Anatomy III, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig-Maximilian-University (LMU), D-82152 Planegg-Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Walenta","sequence":"additional","affiliation":[{"name":"Cell Biology-Anatomy III, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig-Maximilian-University (LMU), D-82152 Planegg-Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2018-9870","authenticated-orcid":false,"given":"Shibojyoti","family":"Lahiri","sequence":"additional","affiliation":[{"name":"Protein Analysis Unit, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig-Maximilian-University (LMU), D-82152 Planegg-Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Imhof","sequence":"additional","affiliation":[{"name":"Protein Analysis Unit, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig-Maximilian-University (LMU), D-82152 Planegg-Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Strauss","sequence":"additional","affiliation":[{"name":"Research Center for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, FI-20300 Turku, Finland"},{"name":"Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, FI-20300 Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matti","family":"Poutanen","sequence":"additional","affiliation":[{"name":"Research Center for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, FI-20300 Turku, Finland"},{"name":"Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, FI-20300 Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9388-4639","authenticated-orcid":false,"given":"Artur","family":"Mayerhofer","sequence":"additional","affiliation":[{"name":"Cell Biology-Anatomy III, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig-Maximilian-University (LMU), D-82152 Planegg-Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1210\/endo.142.6.8211","article-title":"Altered structure and function of reproductive organs in transgenic male mice overexpressing human aromatase","volume":"142","author":"Li","year":"2001","journal-title":"Endocrinology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/S0960-0760(03)00376-5","article-title":"Phenotype characteristics of transgenic male mice expressing human aromatase under ubiquitin C promoter","volume":"86","author":"Li","year":"2003","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lahiri, S., Walenta, L., Aftab, W., Strauss, L., Poutanen, M., Mayerhofer, A., and Imhof, A. (2020). Imaging mass spectrometry and shotgun proteomics reveal dysregulated pathways in hormone induced male infertility. bioRxiv.","DOI":"10.1101\/2020.02.03.931931"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"18334","DOI":"10.1038\/s41598-020-75059-9","article-title":"Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice","volume":"10","author":"Cho","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.2353\/ajpath.2009.081107","article-title":"Increased endogenous estrogen synthesis leads to the sequential induction of prostatic inflammation (prostatitis) and prostatic pre-malignancy","volume":"175","author":"Ellem","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/S0002-9440(10)63191-4","article-title":"Multiple structural and functional abnormalities in the p450 aromatase expressing transgenic male mice are ameliorated by a p450 aromatase inhibitor","volume":"164","author":"Li","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1210\/en.2005-0654","article-title":"Transgenic mice expressing p450 aromatase as a model for male infertility associated with chronic inflammation in the testis","volume":"147","author":"Li","year":"2006","journal-title":"Endocrinology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/S0015-0282(02)03206-5","article-title":"Number, distribution pattern, and identification of macrophages in the testes of infertile men","volume":"78","author":"Frungieri","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1111\/j.1365-2605.2011.01225.x","article-title":"High levels of the extracellular matrix proteoglycan decorin are associated with inhibition of testicular function","volume":"35","author":"Adam","year":"2012","journal-title":"Int. J. Androl."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E2384","DOI":"10.1073\/pnas.1400057111","article-title":"Yolk-sac-derived macrophages regulate fetal testis vascularization and morphogenesis","volume":"111","author":"DeFalco","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1530\/jrf.0.1020393","article-title":"Requirement for testicular macrophages in Leydig cell proliferation and differentiation during prepubertal development in rats","volume":"102","author":"Gaytan","year":"1994","journal-title":"J. Reprod. Fertil."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.celrep.2015.07.015","article-title":"Macrophages Contribute to the Spermatogonial Niche in the Adult Testis","volume":"12","author":"DeFalco","year":"2015","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/j.1600-065X.2006.00438.x","article-title":"The testis in immune privilege","volume":"213","author":"Fijak","year":"2006","journal-title":"Immunol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e12710","DOI":"10.1111\/aji.12710","article-title":"The roles of the PD-1\/PD-L1 pathway at immunologically privileged sites","volume":"78","author":"Wang","year":"2017","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4327","DOI":"10.4049\/jimmunol.1700162","article-title":"Characterization of the Micro-Environment of the Testis that Shapes the Phenotype and Function of Testicular Macrophages","volume":"198","author":"Wang","year":"2017","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1002\/JLB.3MR0318-086RR","article-title":"Microenvironmental signals govern the cellular identity of testicular macrophages","volume":"104","author":"Meinhardt","year":"2018","journal-title":"J. Leukoc. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"110649","DOI":"10.1016\/j.exger.2019.110649","article-title":"Aging in the Syrian hamster testis: Inflammatory-oxidative status and the impact of photoperiod","volume":"124","author":"Matzkin","year":"2019","journal-title":"Exp. Gerontol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4375","DOI":"10.1038\/s41467-020-18206-0","article-title":"Generation, localization and functions of macrophages during the development of testis","volume":"11","author":"Lokka","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2013686117","DOI":"10.1073\/pnas.2013686117","article-title":"Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis","volume":"118","author":"Wang","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5471","DOI":"10.1111\/febs.12302","article-title":"What do we know about the transient receptor potential vanilloid 2 (TRPV2) ion channel?","volume":"280","author":"Gaudet","year":"2013","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/18906","article-title":"A capsaicin-receptor homologue with a high threshold for noxious heat","volume":"398","author":"Caterina","year":"1999","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11425","DOI":"10.1523\/JNEUROSCI.1384-09.2011","article-title":"TRP vanilloid 2 knock-out mice are susceptible to perinatal lethality but display normal thermal and mechanical nociception","volume":"31","author":"Park","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15894","DOI":"10.1074\/jbc.M608287200","article-title":"Activation properties of heterologously expressed mammalian TRPV2: Evidence for species dependence","volume":"282","author":"Neeper","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"35741","DOI":"10.1074\/jbc.M404164200","article-title":"2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3","volume":"279","author":"Hu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6231","DOI":"10.1523\/JNEUROSCI.0504-08.2008","article-title":"TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons","volume":"28","author":"Qin","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0014-2999(88)90356-1","article-title":"The antagonism induced by ruthenium red of the actions of capsaicin on the peripheral terminals of sensory neurons: Further studies","volume":"154","author":"Maggi","year":"1988","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0143-4160(97)90107-X","article-title":"Inhibition of proliferation of MCF-7 breast cancer cells by a blocker of Ca2+-permeable channel","volume":"22","author":"Nie","year":"1997","journal-title":"Cell Calcium"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"24359","DOI":"10.1073\/pnas.1904332116","article-title":"Oxidation of methionine residues activates the high-threshold heat-sensitive ion channel TRPV2","volume":"116","author":"Fricke","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4601","DOI":"10.1523\/JNEUROSCI.5830-09.2010","article-title":"TRPV2 enhances axon outgrowth through its activation by membrane stretch in developing sensory and motor neurons","volume":"30","author":"Shibasaki","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"174","DOI":"10.2337\/db08-0862","article-title":"Regulation of calcium-permeable TRPV2 channel by insulin in pancreatic beta-cells","volume":"58","author":"Hisanaga","year":"2009","journal-title":"Diabetes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1161\/01.RES.0000093204.25499.83","article-title":"Mechanosensitive cation channels in arterial smooth muscle cells are activated by diacylglycerol and inhibited by phospholipase C inhibitor","volume":"93","author":"Park","year":"2003","journal-title":"Circ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1007\/s12272-012-1016-8","article-title":"Quantitative analysis of TRP channel genes in mouse organs","volume":"35","author":"Jang","year":"2012","journal-title":"Arch. Pharm. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1084\/jem.20032082","article-title":"A TRPV2-PKA signaling module for transduction of physical stimuli in mast cells","volume":"200","author":"Stokes","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/jcp.20883","article-title":"Chemotactic peptide fMetLeuPhe induces translocation of the TRPV2 channel in macrophages","volume":"210","author":"Nagasawa","year":"2007","journal-title":"J. Cell Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/ni.1842","article-title":"TRPV2 has a pivotal role in macrophage particle binding and phagocytosis","volume":"11","author":"Link","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"113","DOI":"10.33549\/physiolres.932053","article-title":"Mast-cell degranulation induced by physical stimuli involves the activation of transient-receptor-potential channel TRPV2","volume":"61","author":"Zhang","year":"2012","journal-title":"Physiol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.ceca.2010.09.010","article-title":"RANKL-induced TRPV2 expression regulates osteoclastogenesis via calcium oscillations","volume":"48","author":"Kajiya","year":"2010","journal-title":"Cell Calcium"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.bbrc.2010.06.082","article-title":"Role of transient receptor potential vanilloid 2 in LPS-induced cytokine production in macrophages","volume":"398","author":"Yamashiro","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/11086","article-title":"Translocation of a calcium-permeable cation channel induced by insulin-like growth factor-I","volume":"1","author":"Kanzaki","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1507\/endocrj.49.349","article-title":"Immunohistochemical localization of growth factor-regulated channel (GRC) in human tissues","volume":"49","author":"Kowase","year":"2002","journal-title":"Endocr. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11162","DOI":"10.1073\/pnas.90.23.11162","article-title":"Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene","volume":"90","author":"Lubahn","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1210\/en.2008-1311","article-title":"Increased exposure to estrogens disturbs maturation, steroidogenesis, and cholesterol homeostasis via estrogen receptor alpha in adult mouse Leydig cells","volume":"150","author":"Strauss","year":"2009","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"20030","DOI":"10.1074\/jbc.M116.731216","article-title":"NADPH Oxidases Are Essential for Macrophage Differentiation","volume":"291","author":"Xu","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1042\/CS20150660","article-title":"NOX2-dependent regulation of inflammation","volume":"130","author":"Singel","year":"2016","journal-title":"Clin. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1172\/JCI59901","article-title":"Estrogen promotes Leydig cell engulfment by macrophages in male infertility","volume":"124","author":"Yu","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"15677","DOI":"10.1073\/pnas.95.26.15677","article-title":"Generation and reproductive phenotypes of mice lacking estrogen receptor beta","volume":"95","author":"Krege","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4727\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:55:28Z","timestamp":1760162128000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4727"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,29]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22094727"],"URL":"https:\/\/doi.org\/10.3390\/ijms22094727","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,29]]}}}