Decreased Toll-like Receptor (TLR) 2 and 4 Expression in Spermatozoa in Couples with Unexplained Recurrent Spontaneous Abortion (URSA)
-
Nasrin Sereshki
,
Alireza Andalib
,
Ataollah Ghahiri
,
Ferdos Mehrabian
,
Roya Sherkat
,
Abbas Rezaei
Abstract
Studies have shown that toll-like receptors (TLRs) play some important roles in reproductive processes such as ovulation, spermatogenesis, sperm capacitation, fertilization, and pregnancy to the best of our knowledge, no study has evaluated the expression and role of these molecules and their impairment in spermatozoa; accompanied by pregnancy complications such as recurrent spontaneous abortion (RSA). Therefore, this study investigates the alteration of toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4) expression in spermatozoa in men whose spouse have unexplained RSA. Fifteen fertile couples and fifteen couples with unexplained recurrent spontaneous abortion (URSA) were included in this study. The level of TLR2 and TLR4 expression in untreated and lipopolysaccharide (LPS) or PAM3CYS in treated spermatozoa were examined by flow cytometry. The results showed reduced expression of TLR4 in untreated spermatozoa and decreased LPS or PAM3CYS levels in treated spermatozoa in the URSA group compared to the control group. No significant differences were found in TLR2 expression of untreated spermatozoa in RSA and control groups. After the treatment of spermatozoa with LPS, the TLR2 expression was decreased in both groups. After the treatment of spermatozoa with PAM3CYS, the level of TLR2 expression was significantly increased in the URSA group; while no significant differences were shown in the control group in comparison to untreated spermatozoa. We have concluded that decreased TLR4 expression and a differently increased TLR2 expression in response to ligand treatment in spermatozoa is associated with URSA.
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2. Johansson M, Bromfield JJ, Jasper MJ, Robertson SA. Semen activates the female immune response during early pregnancy in mice. Immunology 2004; 112(2):290-300.
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8. Charles A, Omwandho HR, Tinneberg AG, Tumbo O, Timothy K, Falconer RJ. Recurrent pregnancy losses and the role of immunotherapy. Arch Gynecol Obstet 2000; 264(1):3-12.
9. Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet 2005; 272(2):95-108.
10. Palladino MA, Savarese MA, Chapman JL, Dughi MK, Plaska D. Localization of Toll-Like Receptors on Epididymal Epithelial Cells and Spermatozoa. Am J Reprod Immunol 2008; 60(6):541-55.
11. Saeidi S, Shapouri F, Amirchaghmaghi E, Hoseinifar H, Sabbaghian M, Gilani MAS, et al. Sperm protection in the male reproductive tract by Toll-like receptors. Andrologia 2014; 46(7):784-90.
12. Nardo D-D. Toll-like receptors: Activation, signalling and transcriptional modulation. Cytokine 2015; 74: 181–9.
13. Erridge C. Endogenous ligands of TLR2 and TLR4: agonists or assistants? J Leukoc Biol 2010; 87(6):989-99.
14. Hedger MP. Toll-like receptors and signalling in spermatogenesis and testicular responses to inflammation-a perspective. J Reprod Immunol 2011; 88(2):130-41.
15. Malm J, Nordahl EA, Bjartell A, Sørensen OE, Frohm B, Dentener MA, et al. Lipopolysaccharide-binding protein is produced in the epididymis and associated with spermatozoa and prostasomes. J Reprod Immunol 2005; 66(1):33-43.
16. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol Pharm Bull 2005; 28(5):886–92.
17. McClure R, Massari P. TLR-dependent human mucosal epithelial cell responses to microbial pathogens. Front Immunol 2014; 5:386.
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19. Reid G, Brigidi P, Burton JP, Contractor N, Duncan S, Fargier E, et al. Microbes Central to Human Reproduction. American Journal of Reproductive Immunology. 2015;73(1):1-11.
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22. Organization WH. WHO laboratory manual for the examination and processing of human semen. 2010.
23. Fujita Y, Mihara T, Okazaki T, Shitanaka M, Kushino R, Ikeda C, et al. Toll-like receptors (TLR) 2 and 4 on human sperm recognize bacterial endotoxins and mediate apoptosis. Hum Reprod 2011; 26(10):2799-806.
24. Zhu X, Shi D, Li X, Gong W, Wu F, Guo X, et al. TLR signalling affects sperm mitochondrial function and motility via phosphatidylinositol 3-kinase and glycogen synthase kinase-3α. Cell Signal 2016; 28(3):148-56.
25. Harris HE, Raucci A. Alarmin (g) news about danger: workshop on innate danger signals and HMGB1. EMBO Rep 2006; 7(8):774-8.
26. Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R, et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 2007; 220(1):47-59.
27. Ibrahim ZA, Armour CL, Phipps S, Sukkar MB. RAGE and TLRs: relatives, friends or neighbours? Mol Immunol 2013; 56(4):739-44.
28. Shimada M, Yanai Y, Okazaki T, Noma N, Kawashima I, Mori T, et al. Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine/chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization. Development 2008; 135(11):2001-11.
29. Richards JS, Liu Z, Shimada M. Immune-like mechanisms in ovulation. Trends Endocrinol Metab 2008; 19(6):191-6.
30. Liu Z, Shimada M, Richards JS. The involvement of the Toll-like receptor family in ovulation. J Assist Reprod Genet 2008; 25(6):223-8.
31. Barbonetti A, Vassallo MRC, Pelliccione F, D'Angeli A, Santucci R, Muciaccia B, et al. Beta-chemokine receptor CCR5 in human spermatozoa and its relationship with seminal parameters. Hum Reprod 2009;24(12):2979-87.
32. Muciaccia B, Padula F, Vicini E, Gandini L, Lenzi A, Stefanini M. Beta-chemokine receptors 5 and 3 are expressed on the head region of human spermatozoon. FASEB J 2005; 19(11):2048-50.
33. Isobe T, Minoura H, Tanaka K, Shibahara T, Hayashi N, Toyoda N. The effect of RANTES on human sperm chemotaxis. Hum Reprod 2002; 17(6):1441-6.
34. Caballero‐Campo P, Buffone MG, Benencia F, Conejo‐García JR, Rinaudo PF, Gerton GL. A role for the chemokine receptor CCR6 in mammalian sperm motility and chemotaxis. J Cell Physiol 2014; 229(1):68-78.
2. Johansson M, Bromfield JJ, Jasper MJ, Robertson SA. Semen activates the female immune response during early pregnancy in mice. Immunology 2004; 112(2):290-300.
3. Robertson SA, Sharkey DJ. Seminal fluid and fertility in women. Fertil Steril 2016; 106(3):511-9.
4. Bromfield JJ. Seminal fluid and reproduction: much more than previously thought. J Assist Reprod Genet 2014; 31(6):627-36.
5. Schjenken JE, Robertson SA. Seminal Fluid Signalling in the Female Reproductive Tract: Implications for Reproductive Success and Offspring Health.Adv Exp Med Biol 2015;868:127-58
6. Kverka M, Ulcova-Gallova Z, Bartova J, Cibulka J, Bibkova K, Micanova Z, et al. Sperm Cells Induce Distinct Cytokine Response in Peripheral Mononuclear Cells from Infertile Women with Serum Anti-Sperm Antibodies. Plos One 2012; 7(8).
7. Sereshki N, Gharagozloo M, Ostadi V, Ghahiri A, Roghaei MA, Mehrabian F, et al. Variations in T-helper 17 and regulatory T cells during the menstrual cycle in peripheral blood of women with recurrent spontaneous abortion. Int J Fertil Steril 2014; 8(1):59-66.
8. Charles A, Omwandho HR, Tinneberg AG, Tumbo O, Timothy K, Falconer RJ. Recurrent pregnancy losses and the role of immunotherapy. Arch Gynecol Obstet 2000; 264(1):3-12.
9. Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet 2005; 272(2):95-108.
10. Palladino MA, Savarese MA, Chapman JL, Dughi MK, Plaska D. Localization of Toll-Like Receptors on Epididymal Epithelial Cells and Spermatozoa. Am J Reprod Immunol 2008; 60(6):541-55.
11. Saeidi S, Shapouri F, Amirchaghmaghi E, Hoseinifar H, Sabbaghian M, Gilani MAS, et al. Sperm protection in the male reproductive tract by Toll-like receptors. Andrologia 2014; 46(7):784-90.
12. Nardo D-D. Toll-like receptors: Activation, signalling and transcriptional modulation. Cytokine 2015; 74: 181–9.
13. Erridge C. Endogenous ligands of TLR2 and TLR4: agonists or assistants? J Leukoc Biol 2010; 87(6):989-99.
14. Hedger MP. Toll-like receptors and signalling in spermatogenesis and testicular responses to inflammation-a perspective. J Reprod Immunol 2011; 88(2):130-41.
15. Malm J, Nordahl EA, Bjartell A, Sørensen OE, Frohm B, Dentener MA, et al. Lipopolysaccharide-binding protein is produced in the epididymis and associated with spermatozoa and prostasomes. J Reprod Immunol 2005; 66(1):33-43.
16. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol Pharm Bull 2005; 28(5):886–92.
17. McClure R, Massari P. TLR-dependent human mucosal epithelial cell responses to microbial pathogens. Front Immunol 2014; 5:386.
18. Marcato L, Ferlini A, Bonfim R, Ramos‐Jorge M, Ropert C, Afonso L, et al. The role of Toll‐like receptors 2 and 4 on reactive oxygen species and nitric oxide production by macrophage cells stimulated with root canal pathogens. Oral Microbiol Immunol 2008; 23(5):353-9.
19. Reid G, Brigidi P, Burton JP, Contractor N, Duncan S, Fargier E, et al. Microbes Central to Human Reproduction. American Journal of Reproductive Immunology. 2015;73(1):1-11.
20. Schoenmakers S, Steegers-Theunissen R, Faas M. The matter of the reproductive microbiome. Obstetric Medicine. 2018.
21. Smith SB, Ravel J. The vaginal microbiota, host defence and reproductive physiology. Journal of Physiology-London. 2017;595(2):451-63.
22. Organization WH. WHO laboratory manual for the examination and processing of human semen. 2010.
23. Fujita Y, Mihara T, Okazaki T, Shitanaka M, Kushino R, Ikeda C, et al. Toll-like receptors (TLR) 2 and 4 on human sperm recognize bacterial endotoxins and mediate apoptosis. Hum Reprod 2011; 26(10):2799-806.
24. Zhu X, Shi D, Li X, Gong W, Wu F, Guo X, et al. TLR signalling affects sperm mitochondrial function and motility via phosphatidylinositol 3-kinase and glycogen synthase kinase-3α. Cell Signal 2016; 28(3):148-56.
25. Harris HE, Raucci A. Alarmin (g) news about danger: workshop on innate danger signals and HMGB1. EMBO Rep 2006; 7(8):774-8.
26. Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R, et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 2007; 220(1):47-59.
27. Ibrahim ZA, Armour CL, Phipps S, Sukkar MB. RAGE and TLRs: relatives, friends or neighbours? Mol Immunol 2013; 56(4):739-44.
28. Shimada M, Yanai Y, Okazaki T, Noma N, Kawashima I, Mori T, et al. Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine/chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization. Development 2008; 135(11):2001-11.
29. Richards JS, Liu Z, Shimada M. Immune-like mechanisms in ovulation. Trends Endocrinol Metab 2008; 19(6):191-6.
30. Liu Z, Shimada M, Richards JS. The involvement of the Toll-like receptor family in ovulation. J Assist Reprod Genet 2008; 25(6):223-8.
31. Barbonetti A, Vassallo MRC, Pelliccione F, D'Angeli A, Santucci R, Muciaccia B, et al. Beta-chemokine receptor CCR5 in human spermatozoa and its relationship with seminal parameters. Hum Reprod 2009;24(12):2979-87.
32. Muciaccia B, Padula F, Vicini E, Gandini L, Lenzi A, Stefanini M. Beta-chemokine receptors 5 and 3 are expressed on the head region of human spermatozoon. FASEB J 2005; 19(11):2048-50.
33. Isobe T, Minoura H, Tanaka K, Shibahara T, Hayashi N, Toyoda N. The effect of RANTES on human sperm chemotaxis. Hum Reprod 2002; 17(6):1441-6.
34. Caballero‐Campo P, Buffone MG, Benencia F, Conejo‐García JR, Rinaudo PF, Gerton GL. A role for the chemokine receptor CCR6 in mammalian sperm motility and chemotaxis. J Cell Physiol 2014; 229(1):68-78.
| Files | ||
| Issue | Vol 18, No 6 (2019) | |
| Section | Brief Communication | |
| DOI | https://doi.org/10.18502/ijaai.v18i6.2183 | |
| PMID | 32245314 | |
| Keywords | ||
| Recurrent miscarriage Spermatozoa Toll-like receptor 2 Toll-like receptor 4 | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Sereshki N, Andalib A, Ghahiri A, Mehrabian F, Sherkat R, Rezaei A. Decreased Toll-like Receptor (TLR) 2 and 4 Expression in Spermatozoa in Couples with Unexplained Recurrent Spontaneous Abortion (URSA). Iran J Allergy Asthma Immunol. 2019;18(6):701-706.
