Immune–endocrine interactions in bovine testicular homeostasis: A conceptual framework for reproductive resilience

Immune–endocrine rheostat in bull testes

Authors

  • Fitriani Sultan Masters Program of Reproductive Biology, Faculty of Veterinary Medicince, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0009-0007-6495-6596
  • Ranto Bayu Damanik Masters Program in Veterinary Disease and Public Health, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0009-0001-8229-7797
  • Lita Rakhma Yustinasari Faculty of Veterinary Medicince, Universitas Airlangga, Surabaya, Indonesia
  • Erma Safitri Faculty of Veterinary Medicince, Universitas Airlangga, Surabaya, Indonesia
  • Ragil Angga Prastiya Department of Health and Life Sciences, Faculty of Health, Medicine, and Life Sciences (FIKKIA), Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0000-0003-2658-2099
  • Gracia Angelina Hendarti Faculty of Veterinary Medicince, Universitas Airlangga, Surabaya, Indonesia
  • Sapta Andaruisworo Animal Science Study Program, Faculty of Health and Science, Universitas Nusantara PGRI Kediri, Indonesia https://orcid.org/0000-0002-3013-0215
  • Samira Musa Sasi Developmental Biology Division, Zoology Department, Faculty of Science, University of Tripoli, Libya https://orcid.org/0000-0002-9436-8548
  • Boedi Setiawan Faculty of Veterinary Medicince, Universitas Airlangga, Surabaya, Indonesia
  • Rahmi Sugihartuti Faculty of Veterinary Medicince, Universitas Airlangga, Surabaya, Indonesia
  • Kuncoro Puguh Santoso Faculty of Veterinary Medicince, Universitas Airlangga, Surabaya, Indonesia
  • Gunanti Mahasri Department of Aquaculture, Faculty of Fisheries and Marine, Universitas Airlangga, Surabaya, Indonesia
  • Siti Eliana Rochmi Veterinary Technology Program, Department of Health, Faculty of Vocational Studies, Universitas Airlangga, Surabaya, East Java, Indonesia https://orcid.org/0000-0002-7110-8313
  • Muhammad Munawaroh Department of Basic Medical Veterinary Medicine, Faculty of Veterinary Medicine, Universitas Pendidikan Mandalika, Mataram City, Indonesia.
  • Zaldi Ahmad Department of Islamic Education, Faculty of Islamic Studies, Universitas Islam Nusantara, Indonesia
  • Haris Muhtadi Masters Program in Fisheries Science, Faculty of Fisheries and Marine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0009-0004-0861-1938
  • Vivi Oktaviana Masters Program in Veterinary Agribusiness, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia

DOI:

https://doi.org/10.62310/liab.v6i2.440

Keywords:

Bull fertility, Blood–testis barrier, Leydig cell, Macrophage, Thermoregulation, Reproductive health

Abstract

Bull fertility depends on coordinated regulation of spermatogenesis, endocrine function, immune tolerance, and tissue stress responses. This narrative review synthesizes direct bovine evidence with comparative mammalian mechanisms to evaluate a conceptual framework of coordinated immune–endocrine regulation in testicular homeostasis. At baseline, luteinizing hormone-dependent Leydig-cell steroidogenesis, follicle-stimulating hormone- and androgen-responsive Sertoli-cell functions, resident immune cells, cytokines, redox pathways, and the blood–testis barrier collectively support germ-cell development while limiting damaging immunity. Direct studies in cattle show that this balance is stress sensitive. In Nelore bulls, 48 h of scrotal insulation increased intratesticular temperature from 35.28 to 38.62°C, reduced tissue testosterone from 3,119 to 295.5 ng/g, and markedly suppressed STAR while inducing GPX1 and HSP70. Bovine Sertoli-cell experiments identify TLR4–NF-κB signaling as a causal link between danger sensing, inflammation, mitochondrial injury, and barrier-protein loss. Acute bovine besnoitiosis further demonstrates how vascular injury, inflammatory infiltration, impaired thermoregulation, and germ-cell degeneration can converge in vivo. Recent single-cell and spatial transcriptomic studies now resolve macrophage, T-cell, Leydig-cell, Sertoli-cell, and germ-cell populations in bovine testes, although they do not yet establish causal immune–endocrine communication. Three operational states – homeostatic tolerance, compensated stress, and decompensated inflammation – are used to describe regions of a continuous response spectrum rather than validated, discrete physiological categories. Within this framework, bull subfertility may partly reflect a reduced capacity to maintain coordinated testicular homeostasis. Longitudinal assessment of immune, endocrine, metabolic, and spatial parameters is therefore a priority for further mechanistic validation.

References

Adegoke EO, Wang C, Machebe NS, Wang X, Wang H, Adeniran SO, Zhang H, Zheng P, Zhang G. (2018a). Microcystin-leucine arginine induced inflammatory response in bovine Sertoli cells via TLR4/NF-κB signaling. Environmental Toxicology and Pharmacology 63: 115–126. https://doi.org/10.1016/j.etap.2018.09.001

Adegoke EO, Wang X, Wang H, Wang C, Zhang H, Zhang G. (2018b). Selenium (Na₂SeO₃) upregulates expression of immune genes and blood-testis-barrier constituent proteins of bovine Sertoli cells in vitro. Biological Trace Element Research 185: 332–343. https://doi.org/10.1007/s12011-018-1248-7

Adegoke EO, Adeniran SO, Zeng Y, Wang X, Wang H, Wang C, Zhang H, Zheng P, Zhang G. (2019). Pharmacological inhibition of TLR4/NF-κB with TLR4-IN-C34 attenuated microcystin-LR toxicity in bovine Sertoli cells. Journal of Applied Toxicology 39: 832–843. https://doi.org/10.1002/jat.3771

Allen JA, Diemer T, Janus P, Hales KH, Hales DB. (2005). Bacterial endotoxin lipopolysaccharide and reactive oxygen species inhibit Leydig cell steroidogenesis via perturbation of mitochondria. Endocrine 25: 265–275. https://doi.org/10.1385/ENDO:25:3:265

Alves MG, Rato L, Carvalho RA, Moreira PI, Socorro S, Oliveira PF. (2013). Hormonal control of Sertoli cell metabolism regulates spermatogenesis. Cellular and Molecular Life Sciences 70: 777–793. https://doi.org/10.1007/s00018-012-1079-1

Alves LA, Cooke RF, Sant’Ana Borges M, Souza FF, Kastelic JP, Crespilho AM. (2025). Season and temperature-humidity index affect sperm quality and in vivo fertility of beef bulls. Journal of Thermal Biology 133: 104271. https://doi.org/10.1016/j.jtherbio.2025.104271

Babcock RL, Haynes A, Dufour JM. (2026). Testicular immune privilege revisited: when protection fails. Fertility and Sterility 125(5): 737–745. https://doi.org/10.1016/j.fertnstert.2026.03.018

Bagath M, Krishnan G, Devaraj C, Rashamol VP, Pragna P, Lees AM, Sejian V. (2019). The impact of heat stress on the immune system in dairy cattle: A review. Research in Veterinary Science 126: 94–102. https://doi.org/10.1016/j.rvsc.2019.08.011

Bhushan S, Tchatalbachev S, Lu Y, Fröhlich S, Fijak M, Vijayan V, Chakraborty T, Meinhardt A. (2015). Differential activation of inflammatory pathways in testicular macrophages provides a rationale for their subdued inflammatory capacity. Journal of Immunology 194: 5455–5464. https://doi.org/10.4049/jimmunol.1401132

Boussouar F, Benahmed M. (2004). Lactate and energy metabolism in male germ cells. Trends in Endocrinology & Metabolism 15: 345–350. https://doi.org/10.1016/j.tem.2004.07.003

Bucher K, Malama E, Siuda M, Janett F, Bollwein H. (2019). Multicolor flow cytometric analysis of cryopreserved bovine sperm: a tool for the evaluation of bull fertility. Journal of Dairy Science 102: 11652–11669. https://doi.org/10.3168/jds.2019-16572

Buck MD, Sowell RT, Kaech SM, Pearce EL. (2017). Metabolic instruction of immunity. Cell 169: 570–586. https://doi.org/10.1016/j.cell.2017.04.004

Butler ML, Bormann JM, Weaber RL, Grieger DM, Rolf MM. (2020). Selection for bull fertility: a review. Translational Animal Science 4: 423–441. https://doi.org/10.1093/tas/txz174

Cao Z, Huang W, Sun Y, Li Y. (2020). Deoxynivalenol induced spermatogenesis disorder by blood-testis barrier disruption associated with testosterone deficiency and inflammation in mice. Environmental Pollution 264: 114748. https://doi.org/10.1016/j.envpol.2020.114748

Celeghini ECC, Baatsch-Nascimento F, Bozzi AR, Garcia-Oliveros LN, Arruda RP. (2024). Bovine testicular heat stress: From climate change to effects on microRNA profile. Animal Reproduction Science 270: 107620. https://doi.org/10.1016/j.anireprosci.2024.107620

Chen Q, Deng T, Han D. (2016). Testicular immunoregulation and spermatogenesis. Seminars in Cell & Developmental Biology 59: 157–165. https://doi.org/10.1016/j.semcdb.2016.01.019

Cheng CY, Mruk DD. (2012). The blood-testis barrier and its implications for male contraception. Pharmacological Reviews 64: 16–64. https://doi.org/10.1124/pr.110.002790

Chenoweth PJ, McPherson FJ. (2016). Bull breeding soundness, semen evaluation and cattle productivity. Animal Reproduction Science 169: 32–36. https://doi.org/10.1016/j.anireprosci.2016.03.001

Collier RJ, Collier JL, Rhoads RP, Baumgard LH. (2008). Invited review: genes involved in the bovine heat stress response. Journal of Dairy Science 91: 445–454. https://doi.org/10.3168/jds.2007-0540

Dance A, Thundathil J, Wilde R, Blondin P, Kastelic J. (2015). Enhanced early-life nutrition promotes hormone production and reproductive development in Holstein bulls. Journal of Dairy Science 98: 987–998. https://doi.org/10.3168/jds.2014-8564

Deb R, Sajjanar B, Singh U, Kumar S, Singh R, Sengar G, Sharma A. (2014). Effect of heat stress on the expression profile of Hsp90 among Sahiwal (Bos indicus) and Frieswal (Bos indicus × Bos taurus) breed of cattle: a comparative study. Gene 536: 435–440. https://doi.org/10.1016/j.gene.2013.11.086

DeFalco T, Potter SJ, Williams AV, Waller B, Kan MJ, Capel B. (2015). Macrophages contribute to the spermatogonial niche in the adult testis. Cell Reports 12: 1107–1119. https://doi.org/10.1016/j.celrep.2015.07.015

Diemer T, Hales DB, Weidner W. (2003). Immune-endocrine interactions and Leydig cell function: The role of cytokines. Andrologia 35: 55–63. https://doi.org/10.1046/j.1439-0272.2003.00537.x

Dubey JP, van Wilpe E, Blignaut DJ, Schares G, Williams JH. (2013). Development of early tissue cysts and associated pathology of Besnoitia besnoiti in a naturally infected bull (Bos taurus) from South Africa. Journal of Parasitology 99: 459–466. https://doi.org/10.1645/12-128.1

Esteban-Gil A, Jacquiet P, Florentin S, Decaudin A, Berthelot X, Ronsin P, Grisez C, Prevot F, Alzieu JP, Marois M, Corboz N, Peglion M, Vilardell C, Liénard E, Bouhsira E, Castillo JA, Franc M, Picard-Hagen N. (2016). Does bovine besnoitiosis affect the sexual function of chronically infected bulls? Theriogenology 86: 1325–1332. https://doi.org/10.1016/j.theriogenology.2016.04.074

Fernandes CE, Dode MAN, Pereira D, Silva AEDF. (2008). Effects of scrotal insulation in Nellore bulls (Bos taurus indicus) on seminal quality and its relationship with in vitro fertilizing ability. Theriogenology 70: 1560–1568. https://doi.org/10.1016/j.theriogenology.2008.07.005

Ferrer MS, Palomares RA, Hurley DJ, Norton N, Bullington AC, Hoyos-Jaramillo A, Bittar JHJ. (2022). Changes in serum testosterone and anti-Müllerian hormone concentration in bulls undergoing scrotal insulation. Domestic Animal Endocrinology 78: 106685. https://doi.org/10.1016/j.domaniend.2021.106685

Fijak M, Schneider E, Klug J, Bhushan S, Hackstein H, Schuler G, Wygrecka M, Gromoll J, Meinhardt A. (2011). Testosterone replacement effectively inhibits development of experimental autoimmune orchitis in rats. Journal of Immunology 186: 5162–5172. https://doi.org/10.4049/jimmunol.1001958

Fijak M, Damm LJ, Wenzel JP, Aslani F, Walecki M, Wahle E, Eisel F, Bhushan S, Hackstein H, Baal N, Schuler G, Konrad L, Rafiq A, O'Hara L, Smith LB, Meinhardt A. (2015). Influence of testosterone on inflammatory responses in testicular cells and Foxp3 expression in T cells. American Journal of Reproductive Immunology 74: 12–25. https://doi.org/10.1111/aji.12363

Fomichova O, Oliveira PF, Bernardino RL. (2025). Exploring the interplay between inflammation and male fertility. The FEBS Journal 292: 3321–3349. https://doi.org/10.1111/febs.17366

França LR, Hess RA, Dufour JM, Hofmann MC, Griswold MD. (2016). The Sertoli cell: One hundred fifty years of beauty and plasticity. Andrology 4: 189–212. https://doi.org/10.1111/andr.12165

Frungieri MB, Calandra RS, Mayerhofer A, Matzkin ME. (2015). Cyclooxygenase and prostaglandins in somatic cell populations of the testis. Reproduction 149: R169–R180. https://doi.org/10.1530/REP-14-0392

Gao Y, Bai F, Zhang Q, An X, Wang Z, Lei C, Dang R. (2024). Dynamic transcriptome profiles and novel markers in bovine spermatogenesis revealed by single-cell sequencing. Journal of Integrative Agriculture 23: 2362–2378. https://doi.org/10.1016/j.jia.2023.04.036

Givens MD, Heath AM, Brock KV, Brodersen BW, Carson RL, Stringfellow DA. (2003). Detection of bovine viral diarrhea virus in semen obtained after inoculation of seronegative postpubertal bulls. American Journal of Veterinary Research 64: 428–434. https://doi.org/10.2460/ajvr.2003.64.428

Gong J, Zeng Q, Yu D, Duan YG. (2020). T lymphocytes and testicular immunity: A new insight into immune regulation in testes. International Journal of Molecular Sciences 22: 57. https://doi.org/10.3390/ijms22010057

González-Barrio D, Diezma-Díaz C, Tabanera E, Aguado-Criado E, Pizarro M, González-Huecas M, Ferre I, Jiménez-Meléndez A, Criado F, Gutiérrez-Expósito D, Ortega-Mora LM, Álvarez-García G. (2020). Vascular wall injury and inflammation are key pathogenic mechanisms responsible for early testicular degeneration during acute besnoitiosis in bulls. Parasites & Vectors 13: 113. https://doi.org/10.1186/s13071-020-3959-9

Green CD, Ma Q, Manske GL, Shami AN, Zheng X, Marini S, Moritz L, Sultan C, Gurczynski SJ, Moore BB, Tallquist MD, Li JZ, Hammoud SS. (2018). A comprehensive roadmap of murine spermatogenesis defined by single-cell RNA-seq. Developmental Cell 46: 651–667.e10. https://doi.org/10.1016/j.devcel.2018.07.025

Gross N, Peñagaricano F, Khatib H. (2020). Integration of whole-genome DNA methylation data with RNA sequencing data to identify markers for bull fertility. Animal Genetics 51: 502–510. https://doi.org/10.1111/age.12941

Gu X, Heinrich A, Li SY, DeFalco T. (2023). Testicular macrophages are recruited during a narrow fetal time window and promote organ-specific developmental functions. Nature Communications 14: 1439. https://doi.org/10.1038/s41467-023-37199-0

Gualdoni GS, Jacobo PV, Sobarzo CM, Perez CV, Matzkin ME, Höcht C, Frungieri MB, Hill M, Anegon I, Lustig L, Guazzone VA. (2019). Role of indoleamine 2,3-dioxygenase in testicular immune privilege. Scientific Reports 9: 15919. https://doi.org/10.1038/s41598-019-52192-8

Guo J, Grow EJ, Mlcochova H, Maher GJ, Lindskog C, Nie X, Guo Y, Takei Y, Yun J, Cai L, Kim R, Carrell DT, Goriely A, Hotaling JM, Cairns BR. (2018). The adult human testis transcriptional cell atlas. Cell Research 28: 1141–1157. https://doi.org/10.1038/s41422-018-0099-2

Hansen PJ. (2004). Physiological and cellular adaptations of zebu cattle to thermal stress. Animal Reproduction Science 82–83: 349–360. https://doi.org/10.1016/j.anireprosci.2004.04.011

Harakal J, Qiao H, Wheeler K, Rival C, Paul AGA, Hardy DM, Cheng CY, Goldberg E, Tung KSK. (2022). Exposed and sequestered antigens in testes and their protection by regulatory T-cell-dependent systemic tolerance. Frontiers in Immunology 13: 809247. https://doi.org/10.3389/fimmu.2022.809247

Hedger MP, Meinhardt A. (2003). Cytokines and the immune-testicular axis. Journal of Reproductive Immunology 58: 1–26. https://doi.org/10.1016/S0165-0378(02)00060-8

Jacobo P, Guazzone VA, Theas MS, Lustig L. (2011). Testicular autoimmunity. Autoimmunity Reviews 10: 201–204. https://doi.org/10.1016/j.autrev.2010.09.026

Jha AK, Huang SCC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B, Pearce EJ, Driggers EM, Artyomov MN. (2015). Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42: 419–430. https://doi.org/10.1016/j.immuni.2015.02.005

Jin H, Ma Y, Xie Y, Yang S, Chen X, Wang N, Zhang L, Ma Y. (2026). Dissecting the development of bovine testicular tissue using spatial transcriptomics. Journal of Animal Science and Biotechnology 17: 21. https://doi.org/10.1186/s40104-025-01340-4

Kastelic JP. (2014). Understanding and evaluating bovine testes. Theriogenology 81: 18–23. https://doi.org/10.1016/j.theriogenology.2013.09.001

Kastelic JP, Rizzoto G, Thundathil J. (2018). Testicular vascular cone development and its association with scrotal thermoregulation, semen quality and sperm production in bulls. Animal 12: s133–s141. https://doi.org/10.1017/S1751731118001167

Kaur G, Thompson LA, Dufour JM. (2014). Sertoli cells—Immunological sentinels of spermatogenesis. Seminars in Cell & Developmental Biology 30: 36–44. https://doi.org/10.1016/j.semcdb.2014.02.011

Klein EK, Swegen A, Gunn AJ, Stephen CP, Aitken RJ, Gibb Z. (2022). The future of assessing bull fertility: Can the ‘omics fields identify usable biomarkers? Biology of Reproduction 106(5): 854–864. https://doi.org/10.1093/biolre/ioac031

Kumar A, Ashraf S, Goud TS, Grewal A, Singh SV, Yadav BR, Upadhyay RC. (2015). Expression profiling of major heat shock protein genes during different seasons in cattle (Bos indicus) and buffalo (Bubalus bubalis) under tropical climatic condition. Journal of Thermal Biology 51: 55–64. https://doi.org/10.1016/j.jtherbio.2015.03.006

Ma C, Huang J, Jiang Y, Liu L, Wang N, Huang S, Li H, Zhang X, Wen S, Wang B, Yang S. (2024). Gasdermin D in macrophages drives orchitis by regulating inflammation and antigen presentation processes. EMBO Molecular Medicine 16: 361–385. https://doi.org/10.1038/s44321-023-00016-8

Ma Y, Yu X, Liu YF, Song B, Sun Z, Zhao S. (2025). Immunoregulation and male reproductive function: Impacts and mechanistic insights into inflammation. Andrology 13: 1302–1321. https://doi.org/10.1111/andr.13772

Martinez MS, Motrich RD. (2025). Macrophages in the male genital tract. Biomedical Journal 100910. https://doi.org/10.1016/j.bj.2025.100910

Matsuyama S, Bhushan S, DeFalco T. (2026). Role of macrophages in testis function. Current Topics in Developmental Biology 169: 51–96. https://doi.org/10.1016/bs.ctdb.2026.04.004

Meinhardt A, Wang M, Schulz C, Bhushan S. (2018). Microenvironmental signals govern the cellular identity of testicular macrophages. Journal of Leukocyte Biology 104: 757–766. https://doi.org/10.1002/JLB.3MR0318-086RR

Meng J, Greenlee AR, Taub CJ, Braun RE. (2011). Sertoli-cell-specific deletion of the androgen receptor compromises testicular immune privilege in mice. Biology of Reproduction 85: 254–260. https://doi.org/10.1095/biolreprod.110.090621

Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, Tourlomousis P, Däbritz JHM, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O'Neill LAJ. (2016). Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167: 457–470.e13. https://doi.org/10.1016/j.cell.2016.08.064

Mossadegh-Keller N, Gentek R, Gimenez G, Bigot S, Mailfert S, Sieweke MH. (2017). Developmental origin and maintenance of distinct testicular macrophage populations. Journal of Experimental Medicine 214: 2829–2841. https://doi.org/10.1084/jem.20170829

Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege JL, Mosser DM, Natoli G, Saeij JPJ, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachter JA, Vogel SN, Wynn TA. (2014). Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41: 14–20. https://doi.org/10.1016/j.immuni.2014.06.008

Nes WD, Lukyanenko YO, Jia ZH, Quideau S, Howald WN, Pratum TK, West RR, Hutson JC. (2000). Identification of the lipophilic factor produced by macrophages that stimulates steroidogenesis. Endocrinology 141: 953–958. https://doi.org/10.1210/endo.141.3.7350

Newton R, Priyadharshini B, Turka LA. (2016). Immunometabolism of regulatory T cells. Nature Immunology 17: 618–625. https://doi.org/10.1038/ni.3466

Nichi M, Bols PEJ, Züge RM, Barnabe VH, Goovaerts IGF, Barnabe RC, Cortada CNM. (2006). Seasonal variation in semen quality in Bos indicus and Bos taurus bulls raised under tropical conditions. Theriogenology 66: 822–828. https://doi.org/10.1016/j.theriogenology.2006.01.056

O'Neill LAJ, Kishton RJ, Rathmell J. (2016). A guide to immunometabolism for immunologists. Nature Reviews Immunology 16: 553–565. https://doi.org/10.1038/nri.2016.70

Paul C, Teng S, Saunders PTK. (2009). A single, mild, transient scrotal heat stress causes hypoxia and oxidative stress in mouse testes, which induces germ cell death. Biology of Reproduction 80: 913–919. https://doi.org/10.1095/biolreprod.108.071779

Pearce EJ, O'Neill LAJ. (2016). Immunometabolism governs dendritic cell and macrophage function. Journal of Experimental Medicine 213: 15–23. https://doi.org/10.1084/jem.20151570

Peng W, Kepsch A, Kracht TO, Hasan H, Wijayarathna R, Wahle E, Pleuger C, Bhushan S, Günther S, Kauerhof AC, Planinić A, Fietz D, Schuppe HC, Wygrecka M, Loveland KL, Ježek D, Meinhardt A, Hedger MP, Fijak M. (2022). Activin A and CCR2 regulate macrophage function in testicular fibrosis caused by experimental autoimmune orchitis. Cellular and Molecular Life Sciences 79: 602. https://doi.org/10.1007/s00018-022-04632-4

Qu N, Ogawa Y, Kuramasu M, Nagahori K, Sakabe K, Itoh M. (2020). Immunological microenvironment in the testis. Reproductive Medicine and Biology 19: 24–31. https://doi.org/10.1002/rmb2.12293

Ramaswamy S, Weinbauer GF. (2014). Endocrine control of spermatogenesis: Role of FSH and LH/testosterone. Spermatogenesis 4: e996025. https://doi.org/10.1080/21565562.2014.996025

Ramesha KP, Mol P, Kannegundla U, et al. (2020). Deep proteome profiling of semen of Indian indigenous Malnad Gidda (Bos indicus) cattle. Journal of Proteome Research 19: 3364–3376. https://doi.org/10.1021/acs.jproteome.0c00237

Rato L, Alves MG, Socorro S, Duarte AI, Cavaco JE, Oliveira PF. (2012). Metabolic regulation is important for spermatogenesis. Nature Reviews Urology 9: 330–338. https://doi.org/10.1038/nrurol.2012.77

Rizzoto G, Ferreira JCP, Codognoto VM, Oliveira KC, Mogollón García HD, Pupulim AGR, Teixeira-Neto FJ, Castilho A, Nunes SG, Thundathil JC, Kastelic JP. (2020). Testicular hyperthermia reduces testosterone concentrations and alters gene expression in testes of Nelore bulls. Theriogenology 152: 64–68. https://doi.org/10.1016/j.theriogenology.2020.04.029

Rockett JC, Mapp FL, Garges JB, Luft JC, Mori C, Dix DJ. (2001). Effects of hyperthermia on spermatogenesis, apoptosis, gene expression, and fertility in adult male mice. Biology of Reproduction 65: 229–239. https://doi.org/10.1095/biolreprod65.1.229

Shami AN, Zheng X, Munyoki SK, Ma Q, Manske GL, Green CD, Sukhwani M, Orwig KE, Li JZ, Hammoud SS. (2020). Single-cell RNA sequencing of human, macaque, and mouse testes uncovers conserved and divergent features of mammalian spermatogenesis. Developmental Cell 54: 529–547.e12. https://doi.org/10.1016/j.devcel.2020.05.010

Smith LB, Walker WH. (2014). The regulation of spermatogenesis by androgens. Seminars in Cell & Developmental Biology 30: 2–13. https://doi.org/10.1016/j.semcdb.2014.02.012

Song K, Yang X, An G, Xia X, Zhao J, Xu X, Wan C, Liu T, Zheng Y, Ren S, Wang M, Chang G, Cronin SJF, Penninger JM, Jing T, Ou X, Rao S, Liu Z, Zhao XY. (2022). Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models. Nature Communications 13: 7335. https://doi.org/10.1038/s41467-022-34990-3

Stanton PG. (2016). Regulation of the blood-testis barrier. Seminars in Cell & Developmental Biology 59: 166–173. https://doi.org/10.1016/j.semcdb.2016.06.018

Staub C, Johnson L. (2018). Review: Spermatogenesis in the bull. Animal 12: s27–s35. https://doi.org/10.1017/S1751731118000435

Walecki M, Eisel F, Klug J, Baal N, Paradowska-Dogan A, Wahle E, et al. (2015). Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T cells. Molecular Biology of the Cell 26: 2845–2857. https://doi.org/10.1091/mbc.E14-08-1323

Wang M, Fijak M, Hossain H, Markmann M, Nüsing RM, Lochnit G, et al. (2017). Characterization of the microenvironment of the testis that shapes the phenotype and function of testicular macrophages. Journal of Immunology 198: 4327–4340. https://doi.org/10.4049/jimmunol.1700162

Wang M, Yang Y, Cansever D, Wang Y, Kantores C, Messiaen S, Moison D, Livera G, Chakarov S, Weinberger T, Stremmel C, Fijak M, Klein B, Pleuger C, Lian Z, Ma W, Liu Q, Klee K, Händler K, Ulas T, Schlitzer A, Schultze JL, Becher B, Greter M, Liu Z, Ginhoux F, Epelman S, Schulz C, Meinhardt A, Bhushan S. (2021). Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis. Proceedings of the National Academy of Sciences of the United States of America 118: e2013686117. https://doi.org/10.1073/pnas.2013686117

Wang X, Yang C, Wei X, Zhang Y, Xiao Y, Wang J, Jiang Q, Ju Z, Gao Y, Li Y, Gao Y, Huang J. (2024). Single-cell RNA sequencing reveals the critical role of alternative splicing in cattle testicular spermatogonia. Biology Direct 19: 145. https://doi.org/10.1186/s13062-024-00579-7

Wang X, Jiang F, Yang H, Niu D, Xi H. (2026). Advances in understanding the dual roles of testicular immune responses: From immune privilege to inflammation. Seminars in Immunopathology 48(1): 7. https://doi.org/10.1007/s00281-026-01073-0

Wanjari UR, Gopalakrishnan AV. (2023). A review on immunological aspects in male reproduction: Immune cells and cytokines. Journal of Reproductive Immunology 158: 103984. https://doi.org/10.1016/j.jri.2023.103984

Winnall WR, Muir JA, Hedger MP. (2011). Rat resident testicular macrophages have an alternatively activated phenotype and constitutively produce interleukin-10 in vitro. Journal of Leukocyte Biology 90: 133–143. https://doi.org/10.1189/jlb.1010557

Wong CH, Cheng CY. (2005). The blood-testis barrier: its biology, regulation, and physiological role in spermatogenesis. Current Topics in Developmental Biology 71: 263–296. https://doi.org/10.1016/S0070-2153(05)71008-5

Ye L, Huang W, Liu S, Cai S, Hong L, Xiao W, Thiele K, Zeng Y, Song M, Diao L. (2021). Impacts of immunometabolism on male reproduction. Frontiers in Immunology 12: 658432. https://doi.org/10.3389/fimmu.2021.658432

Yee JB, Hutson JC. (1985). Effects of testicular macrophage-conditioned medium on Leydig cells in culture. Endocrinology 116: 2682–2684. https://doi.org/10.1210/endo-116-6-2682

Zhao S, Zhu W, Xue S, Han D. (2014). Testicular defense systems: Immune privilege and innate immunity. Cellular & Molecular Immunology 11: 428–437. https://doi.org/10.1038/cmi.2014.38

Zirkin BR, Papadopoulos V. (2018). Leydig cells: Formation, function, and regulation. Biology of Reproduction 99: 101–111. https://doi.org/10.1093/biolre/ioy059

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Published

13-10-2026

How to Cite

Sultan, F., Damanik, R. B. ., Yustinasari, L. R. ., Safitri, E., Prastiya, R. A. ., Hendarti, G. A., Andaruisworo, S. ., Sasi, S. M. ., Setiawan, B. ., Sugihartuti, R. ., Santoso, K. P. ., Mahasri, G., Rochmi, S. E. ., Munawaroh, M., Ahmad, Z., Muhtadi, H., & Oktaviana, V. (2026). Immune–endocrine interactions in bovine testicular homeostasis: A conceptual framework for reproductive resilience: Immune–endocrine rheostat in bull testes. Letters in Animal Biology, 6(2), 154–166. https://doi.org/10.62310/liab.v6i2.440

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Section

Review Articles
Recieved 2026-09-12
Accepted 2026-10-08
Published 2026-10-13

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