Testicular inflammation in male reproductive system

Abstract

The control of the immune system, neuroendocrine system, and energy metabolism is essential for the physiological process of male reproduction. The hypothalamic-pituitary-testicular (HPT) axis regulates the generation of gonadal steroid hormones in the testes, which in turn controls spermatogenesis. For the growth and maturation of germ cells, the immune cells and cytokines in the testes offer a safe microenvironment. The cellular reactions and metabolic activities in the testes produce energy and biosynthetic precursors that control the growth of germ cells, as well as testicular immunology and inflammation. Both inflammatory and anti-inflammatory responses depend on immune cell metabolism, which is thought to influence testicular spermatogenesis. The significance of immunometabolism in male reproduction will be underlined in this review.

Keywords

Neuroendocrine / HPT / immunometabolism / spermatogenesis / cytokines

References

[1] Cheng CY, Mruk DD. The blood-testis barrier and its implications for male contraception. Pharmacol Rev. 2012; 64: 16-64.

[2] Bronson R. Biology of the male reproductive tract: its cellular and morphological considerations. Am J Reprod Immunol. 2011; 65: 212-9.

[3] Ye L, Huang W, Liu S, Cai S, Hong L, Xiao W, et al. Impacts of Immunometabolism on Male Reproduction. Front Immunol. 2021; 12: 658432.

[4] Arck P, Solano ME, Walecki M, Meinhardt A. The immune privilege of testis and gravid uterus: same difference? Mol Cell Endocrinol. 2014; 382: 509-20.

[5] Stanton PG. Regulation of the blood-testis barrier. Semin Cell Dev Biol. 2016; 59: 166-73.

[6] Amann RP. The cycle of the seminiferous epithelium in humans: a need to revisit? J Androl. 2008; 29: 469-87.

[7] Yan HH, Mruk DD, Lee WM, Cheng CY. Ectoplasmic specialization: a friend or a foe of spermatogenesis? Bioessays. 2007; 29: 36-48.

[8] Saling PM. Development of the ability to bind to zonae pellucidae during epididymal maturation: reversible immobilization of mouse-spermatozoa by lanthanum. Biol Reprod. 1982; 26: 429-36.

[9] O’Connor AE, De Kretser DM. Inhibins in normal male physiology. Semin Reprod Med. 2004; 22: 177-85.

[10] Knobil E, Neill JD, editors. The Physiology of Reproduction. 2nd ed. New York: Raven Press; 1994.

[11] Bronson R, Peresleni T, Golightly M, Preissner K. Vitronectin is sequestered within human spermatozoa and liberated following the acrosome reaction. Mol Hum Reprod. 2000; 6: 977-82.

[12] Grace KS, Bronson RA, Ghebrehiwet B. Surface expression of complement receptor gC1q-R/p33 is increased on the plasma membrane of human spermatozoa after capacitation. Biol Reprod. 2002; 66: 823-9.

[13] Patrat C, Auer J, Fauque P, Leandri RL, Jouannet P, Serres C. Zona pellucida from fertilised human oocytes induces a voltage-dependent calcium influx and the acrosome reaction in spermatozoa, but cannot be penetrated by sperm. BMC Dev Biol. 2006; 6: 59.

[14] Ducibella T. The cortical reaction and development of activation competence in mammalian oocytes. Hum Reprod Update. 1996; 2: 29-42.

[15] Jiang Q, Han D. Infectious and Immunological Aspects of Male Infertility. In: Simoni M, Huhtaniemi IT, editors. Endocrinology of the Testis and Male Reproduction. Cham: Springer International Publishing; 2017. pp. 1051-69.

[16] Lutton B, Callard I. Evolution of reproductive-immune interactions. Integr Comp Biol. 2006; 46: 1060-71.

[17] Wanjari UR, Gopalakrishnan AV. A review on immunological aspects in male reproduction: An immune cells and cytokines. J Reprod Immunol. 2023; 158: 103984.

[18] Eaton SA, Sethi JK. Immunometabolic Links between Estrogen, Adipose Tissue and Female Reproductive Metabolism. Biology (Basel). 2019; 8: 8.

[19] Stathopoulou C, Nikoleri D, Bertsias G. Immunometabolism: an overview and therapeutic prospects in autoimmune diseases. Immunotherapy. 2019; 11: 813-29.

[20] Plant TM. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-pituitary-gonadal axis. J Endocrinol. 2015; 226: T41-54.

[21] Dhole B, Kumar A. Hypothalamic-Pituitary-Testicular Axis. In: Kumar A, Sharma M, editors. Basics of Human Andrology: A Textbook. Singapore: Springer Singapore; 2017. pp. 117-34.

[22] Rezzani R, Franco C, Hardeland R, Rodella LF. Thymus-Pineal Gland Axis: Revisiting Its Role in Human Life and Ageing. Int J Mol Sci. 2020; 21: 8806.

[23] Boussouar F, Benahmed M. Lactate and energy metabolism in male germ cells. Trends Endocrinol Metab. 2004; 15: 345-50.

[24] Rato L, Alves MG, Socorro S, Duarte AI, Cavaco JE, Oliveira PF. Metabolic regulation is important for spermatogenesis. Nat Rev Urol. 2012; 9: 330-8.

[25] Oliveira PF, Alves MG. Sertoli Cell Metabolism and Spermatogenesis. 1st ed. Cham: Springer International Publishing; 2015.

[26] Oliveira PF, Alves MG, Rato L, Silva J, Sá R, Barros A, et al. Influence of 5α-dihydrotestosterone and 17β-estradiol on human Sertoli cells metabolism. Int J Androl. 2011; 34: e612-20.

[27] Raut S, Kumar AV, Deshpande S, Khambata K, Balasinor NH. Sex hormones regulate lipid metabolism in adult Sertoli cells: A genome-wide study of estrogen and androgen receptor binding sites. J Steroid Biochem Mol Biol. 2021; 211: 105898.

[28] Zirkin BR, Papadopoulos V. Leydig cells: formation, function, and regulation. Biol Reprod. 2018; 99: 101-11.

[29] Alves MG, Rato L, Carvalho RA, Moreira PI, Socorro S, Oliveira PF. Hormonal control of Sertoli cell metabolism regulates spermatogenesis. Cell Mol Life Sci. 2013; 70: 777-93.

[30] Bhatia A, Sekhon HK, Kaur G. Sex hormones and immune dimorphism. ScientificWorldJournal. 2014; 2014: 159150.

[31] Segner H, Verburg-van Kemenade BML, Chadzinska M. The immunomodulatory role of the hypothalamus-pituitary-gonad axis: Proximate mechanism for reproduction-immune trade offs? Dev Comp Immunol. 2017; 66: 43-60.

[32] Tanriverdi F, Gonzalez-Martinez D, Silveira LF, Hu Y, Maccoll GS, Travers P, et al. Expression of gonadotropin-releasing hormone type-I (GnRH-I) and type-II (GnRH-II) in human peripheral blood mononuclear cells (PMBCs) and regulation of B-lymphoblastoid cell proliferation by GnRH-I and GnRH-II. Exp Clin Endocrinol Diabetes. 2004; 112: 587-94.

[33] Morale MC, Batticane N, Bartoloni G, Guarcello V, Farinella Z, Galasso MG, et al. Blockade of central and peripheral luteinizing hormone-releasing hormone (LHRH) receptors in neonatal rats with a potent LHRH-antagonist inhibits the morphofunctional development of the thymus and maturation of the cell-mediated and humoral immune responses. Endocrinology. 1991; 128: 1073-85.

[34] Chen HF, Jeung EB, Stephenson M, Leung PC. Human peripheral blood mononuclear cells express gonadotropin-releasing hormone (GnRH), GnRH receptor, and interleukin-2 receptor γ-chain messenger ribonucleic acids that are regulated by GnRH in vitro . J Clin Endocrinol Metab. 1999; 84: 743-50.

[35] Tanriverdi F, Silveira LF, MacColl GS, Bouloux PM. The hypothalamic-pituitary-gonadal axis: immune function and autoimmunity. J Endocrinol. 2003; 176: 293-304.

[36] Carbone F, Procaccini C, De Rosa V, Alviggi C, De Placido G, Kramer D, et al. Divergent immunomodulatory effects of recombinant and urinary-derived FSH, LH, and hCG on human CD4⁺ T cells . J Reprod Immunol. 2010; 85: 172-9.

[37] Yesilova Z, Ozata M, Kocar IH, Turan M, Pekel A, Sengul A, et al. The effects of gonadotropin treatment on the immunological features of male patients with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2000; 85: 66-70.

[38] Roved J, Westerdahl H, Hasselquist D. Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences. Horm Behav. 2017; 88: 95-105.

[39] Meng J, Greenlee AR, Taub CJ, Braun RE. Sertoli cell-specific deletion of the androgen receptor compromises testicular immune privilege in mice. Biol Reprod. 2011; 85: 254-60.

[40] Ben-Batalla I, Vargas-Delgado ME, von Amsberg G, Janning M, Loges S. Influence of Androgens on Immunity to Self and Foreign: Effects on Immunity and Cancer. Front Immunol. 2020; 11: 1184.

[41] Fijak M, Schneider E, Klug J, Bhushan S, Hackstein H, Schuler G, et al. Testosterone replacement effectively inhibits the development of experimental autoimmune orchitis in rats: evidence for a direct role of testosterone on regulatory T cell expansion. J Immunol. 2011; 186: 5162-72.

[42] Fijak M, Damm LJ, Wenzel JP, Aslani F, Walecki M, Wahle E, et al. Influence of Testosterone on Inflammatory Response in Testicular Cells and Expression of Transcription Factor Foxp3 in T Cells. Am J Reprod Immunol. 2015; 74: 12-25.

[43] Vancolen S, Sébire G, Robaire B. Influence of androgens on the innate immune system. Andrology. 2023; 11: 1237-44.

[44] Cunningham M, Gilkeson G. Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol. 2011; 40: 66-73.

[45] Giefing-Kröll C, Berger P, Lepperdinger G, Grubeck-Loebenstein B. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell. 2015; 14: 309-21.

[46] Yu W, Zheng H, Lin W, Tajima A, Zhang Y, Zhang X, et al. Estrogen promotes Leydig cell engulfment by macrophages in male infertility. J Clin Invest. 2014; 124: 2709-21.

[47] Numan MS, Amiable N, Brown JP, Michou L. Paget’s disease of bone: an osteoimmunological disorder? Drug Des Devel Ther. 2015; 9: 4695-707.

[48] Zhao S, Zhu W, Xue S, Han D. Testicular defense systems: immune privilege and innate immunity. Cell Mol Immunol. 2014; 11: 428-37.

[49] Wang M, Fijak M, Hossain H, Markmann M, Nüsing RM, Lochnit G, et al. Characterization of the Micro-Environment of the Testis that Shapes the Phenotype and Function of Testicular Macrophages. J Immunol. 2017; 198: 4327-40.

[50] Meinhardt A, Wang M, Schulz C, Bhushan S. Microenvironmental signals govern the cellular identity of testicular macrophages. J Leukoc Biol. 2018; 104: 757-66.

[51] Allahveisi A, Afradiasbagharani P, Bazrafkan M, Kafaeinezhad R, Hosseini E. A narrative literature review of remaining male reproductive health concerns as an aspect of persistent/late-onset complications of COVID-19. Middle East Fertil Soc J. 2023; 28: 30.

[52] Ponte R, Dupuy FP, Brimo F, Mehraj V, Brassard P, Belanger M, et al. ; ORCHID study group. Characterization of myeloid cell populations in human testes collected after sex reassignment surgery. J Reprod Immunol. 2018; 125: 16-24.

[53] Wang M, Yang Y, Cansever D, Wang Y, Kantores C, Messiaen S, et al. Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis. Proc Natl Acad Sci U S A. 2021; 118: e2013686117.

[54] Toocheck C, Clister T, Shupe J, Crum C, Ravindranathan P, Lee TK, et al. Mouse Spermatogenesis Requires Classical and Nonclassical Testosterone Signaling. Biol Reprod. 2016; 94: 11.

[55] Martins AD, Alves MG, Simões VL, Dias TR, Rato L, Moreira PI, et al. Control of Sertoli cell metabolism by sex steroid hormones is mediated through modulation in glycolysis-related transporters and enzymes. Cell Tissue Res. 2013; 354: 861-8.

[56] DeFalco T, Potter SJ, Williams AV, Waller B, Kan MJ, Capel B. Macrophages Contribute to the Spermatogonial Niche in the Adult Testis. Cell Rep. 2015; 12: 1107-19.

[57] Wang P, Duan YG. The role of dendritic cells in male reproductive tract. Am J Reprod Immunol. 2016; 76: 186-92.

[58] O’Neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med. 2016; 213: 15-23.

[59] Liu Y, Liang X, Dong W, Fang Y, Lv J, Zhang T, et al. Tumor-Repopulating Cells Induce PD-1 Expression in CD8⁺ T Cells by Transferring Kynurenine and AhR Activation . Cancer Cell. 2018; 33: 480-94.e7.

[60] Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol. 2011; 12: 870-8.

[61] Gualdoni GS, Jacobo PV, Sobarzo CM, Pérez CV, Matzkin ME, Höcht C, et al. Role of indoleamine 2,3-dioxygenase in testicular immune-privilege. Sci Rep. 2019; 9: 15919.

[62] Fijak M, Meinhardt A. The testis in immune privilege. Immunol Rev. 2006; 213: 66-81.

[63] Kelly B, O’Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015; 25: 771-84.

[64] Wang J, Wreford NG, Lan HY, Atkins R, Hedger MP. Leukocyte populations of the adult rat testis following removal of the Leydig cells by treatment with ethane dimethane sulfonate and subcutaneous testosterone implants. Biol Reprod. 1994; 51: 551-61.

[65] Gong J, Zeng Q, Yu D, Duan YG. T Lymphocytes and Testicular Immunity: A New Insight into Immune Regulation in Testes. Int J Mol Sci. 2021; 22: 57.

[66] Wheeler K, Tardif S, Rival C, Luu B, Bui E, Del Rio R, et al. Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy. Proc Natl Acad Sci U S A. 2011; 108: 7511-6.

[67] Hedger MP, Wang J, Lan HY, Atkins RC, Wreford NG. Immunoregulatory activity in adult rat testicular interstitial fluid: relationship with intratesticular CD8⁺ lymphocytes following treatment with ethane dimethane sulfonate and testosterone implants . Biol Reprod. 1998; 58: 935-42.

[68] Poznanski SM, Barra NG, Ashkar AA, Schertzer JD. Immunometabolism of T cells and NK cells: metabolic control of effector and regulatory function. Inflamm Res. 2018; 67: 813-28.

[69] Jacobo P. The role of regulatory T Cells in autoimmune orchitis. Andrologia. 2018; 50: e13092.

[70] Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science. 2016; 354: 481-4.

[71] Beldi-Ferchiou A, Lambert M, Dogniaux S, Vély F, Vivier E, Olive D, et al. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget. 2016; 7: 72961-77.

[72] Mayerhofer A, Walenta L, Mayer C, Eubler K, Welter H. Human testicular peritubular cells, mast cells and testicular inflammation. Andrologia. 2018; 50: e13055.

[73] Caslin HL, Taruselli MT, Haque T, Pondicherry N, Baldwin EA, Barnstein BO, et al. Inhibiting Glycolysis and ATP Production Attenuates IL-33-Mediated Mast Cell Function and Peritonitis. Front Immunol. 2018; 9: 3026.

[74] Van den Bossche J, Baardman J, Otto NA, van der Velden S, Neele AE, van den Berg SM, et al. Mitochondrial Dysfunction Prevents Repolarization of Inflammatory Macrophages. Cell Rep. 2016; 17: 684-96.

[75] Gerendai I, Banczerowski P, Csernus V. Interleukin 1-β injected into the testis acutely stimulates and later attenuates testicular steroidogenesis of the immature rat. Endocrine. 2005; 28: 165-70.

[76] Bisht S, Faiq M, Tolahunase M, Dada R. Oxidative stress and male infertility. Nat Rev Urol. 2017; 14: 470-85.

[77] Hotamisligil GS. Foundations of Immunometabolism and Implications for Metabolic Health and Disease. Immunity. 2017; 47: 406-20.

[78] Ochsendorf FR. Infections in the male genital tract and reactive oxygen species. Hum Reprod Update. 1999; 5: 399-420.

[79] Jacobo P, Guazzone VA, Theas MS, Lustig L. Testicular autoimmunity. Autoimmun Rev. 2011; 10: 201-4.

[80] Barati E, Nikzad H, Karimian M. Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management. Cell Mol Life Sci. 2020; 77: 93-113.

[81] Lainez NM, Coss D. Obesity, Neuroinflammation, and Reproductive Function. Endocrinology. 2019; 160: 2719-36.

[82] Craig JR, Jenkins TG, Carrell DT, Hotaling JM. Obesity, male infertility, and the sperm epigenome. Fertil Steril. 2017; 107: 848-59.

[83] Leisegang K, Henkel R, Agarwal A. Obesity and metabolic syndrome associated with systemic inflammation and the impact on the male reproductive system. Am J Reprod Immunol. 2019; 82: e13178.

[84] Dutta S, Majzoub A, Agarwal A. Oxidative stress and sperm function: A systematic review on evaluation and management. Arab J Urol. 2019; 17: 87-97.

[85] Street EJ, Justice ED, Kopa Z, Portman MD, Ross JD, Skerlev M, et al. The 2016 European guideline on the management of epididymo-orchitis. Int J STD AIDS. 2017; 28: 744-9.

[86] Guzik TJ, Cosentino F. Epigenetics and Immunometabolism in Diabetes and Aging. Antioxid Redox Signal. 2018; 29: 257-74.

[87] Salehi B, Martorell M, Arbiser JL, Sureda A, Martins N, Maurya PK, et al. Antioxidants: Positive or Negative Actors? Biomolecules. 2018; 8: 124.

[88] Dutta S, Sengupta P, Slama P, Roychoudhury S. Oxidative Stress, Testicular Inflammatory Pathways, and Male Reproduction. Int J Mol Sci. 2021; 22: 10043.

[89] Martins AD, Majzoub A, Agawal A. Metabolic Syndrome and Male Fertility. World J Mens Health. 2019; 37: 113-27.

[90] Majzoub A, Agarwal A. Systematic review of antioxidant types and doses in male infertility: Benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. Arab J Urol. 2018; 16: 113-24.

[91] Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2019; 3: CD007411.

[92] Francomano D, Ilacqua A, Bruzziches R, Lenzi A, Aversa A. Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology. 2014; 83: 167-74.

[93] Diaz A, Romero M, Vazquez T, Lechner S, Blomberg BB, Frasca D. Metformin improves in vivo and in vitro B cell function in individuals with obesity and Type-2 Diabetes . Vaccine. 2017; 35: 2694-700.

[94] Tavares RS, Escada-Rebelo S, Silva AF, Sousa MI, Ramalho-Santos J, Amaral S. Antidiabetic therapies and male reproductive function: where do we stand? Reproduction. 2018; 155: R13-37.

[95] Pålsson-McDermott EM, O’Neill LAJ. Targeting immunometabolism as an anti-inflammatory strategy. Cell Res. 2020; 30: 300-14.

[96] Zhang L, Liu Y, Chen XG, Zhang Y, Chen J, Hao ZY, et al. MicroRNA expression profile in chronic nonbacterial prostatitis revealed by next-generation small RNA sequencing. Asian J Androl. 2019; 21: 351-9.

[97] Jaffar M, Ashraf M. Does Weight Loss improve Fertility with respect to Semen Parameters-Results from a Large Cohort Study. Int J Infertil Fetal Med. 2017; 8: 12-7.

[98] Winter AG, Zhao F, Lee RK. Androgen deficiency and metabolic syndrome in men. Transl Androl Urol. 2014; 3: 50-8.

[99] Vabret N, Britton GJ, Gruber C, Hegde S, Kim J, Kuksin M, et al. ; Sinai Immunology Review Project. Immunology of COVID-19: Current State of the Science. Immunity. 2020; 52: 910-41.

[100] Hedger MP, Meinhardt A. Local regulation of T cell numbers and lymphocyte-inhibiting activity in the interstitial tissue of the adult rat testis. J Reprod Immunol. 2000; 48: 69-80.

[101] Crisóstomo L, Alves MG, Gorga A, Sousa M, Riera MF, Galardo MN, et al. Molecular Mechanisms and Signaling Pathways Involved in the Nutritional Support of Spermatogenesis by Sertoli Cells. Methods Mol Biol. 2018; 1748: 129-55.

[102] Frungieri MB, Calandra RS, Mayerhofer A, Matzkin ME. Cyclooxygenase and prostaglandins in somatic cell populations of the testis. Reproduction. 2015; 149: R169-80.

[103] Cardoso AM, Alves MG, Mathur PP, Oliveira PF, Cavaco JE, Rato L. Obesogens and male fertility. Obes Rev. 2017; 18: 109-25.

[104] Pereira SC, Crisóstomo L, Sousa M, Oliveira PF, Alves MG. Metabolic diseases affect male reproduction and induce signatures in gametes that may compromise the offspring health. Environ Epigenet. 2020; 6: dvaa019.

[105] Luo D, Zhang M, Su X, Liu L, Zhou X, Zhang X, et al. High fat diet impairs spermatogenesis by regulating glucose and lipid metabolism in Sertoli cells. Life Sci. 2020; 257: 118028.