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Contrasting effects of the Toll-like receptor 4 in determining ovarian follicle endowment and fertility in female adult mice

Published online by Cambridge University Press:  18 August 2021

Júlio Panzera Gonçalves ,
Breno Augusto Magalhães Open the ORCID record for Breno Augusto Magalhães [Opens in a new window]  and
Paulo Henrique Almeida Campos-Junior Open the ORCID record for Paulo Henrique Almeida Campos-Junior [Opens in a new window]
Júlio Panzera Gonçalves
Affiliation:
Departamento de Ciências Naturais, Universidade Federal de São João del Rei. Praça Dom Helvécio, 74 – Dom Bosco, São João del Rei, MG, 36301-160, Brazil
Breno Augusto Magalhães
Affiliation:
Departamento de Ciências Naturais, Universidade Federal de São João del Rei. Praça Dom Helvécio, 74 – Dom Bosco, São João del Rei, MG, 36301-160, Brazil
Paulo Henrique Almeida Campos-Junior*
Affiliation:
Departamento de Ciências Naturais, Universidade Federal de São João del Rei. Praça Dom Helvécio, 74 – Dom Bosco, São João del Rei, MG, 36301-160, Brazil
*
Author for correspondence: Paulo Henrique Almeida Campos-Junior, Departamento de Ciências Naturais, Universidade Federal de São João del Rei. Praça Dom Helvécio, 74 – Dom Bosco, São João del Rei, MG, 36301-160, Brazil. E-mail: paulohenrique@ufsj.edu.br
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Abstract

Toll-like receptor 4 (TLR4) is best known for its role in bacteria-produced lipopolysaccharide recognition. Regarding female reproduction, TLR4 is expressed by murine cumulus cells and participates in ovulation and in cumulus–oocyte complex (COC) expansion, maternal–fetal interaction and preterm labour. Despite these facts, the role of TLR4 in ovarian physiology is not fully understood. Therefore, the aim of the present study was to investigate the effects of TLR4 genetic ablation on mice folliculogenesis and female fertility, through analysis of reproductive crosses, ovarian responsiveness and follicular quantification in TLR4−/− (n = 94) and C57BL/6 mice [wild type (WT), n = 102]. TLR4-deficient pairs showed a reduced number of pups per litter (P = 0.037) compared with WT. TLR4−/− mice presented more primordial, primary, secondary and antral follicles (P < 0.001), however there was no difference in estrous cyclicity (P > 0.05). A lower (P = 0.006) number of COC was recovered from TLR4−/− mice oviducts after superovulation, and in heterozygous pairs, TLR4−/− females also showed a reduction in the pregnancy rate and in the number of fetuses per uterus (P = 0.007) when compared with WT. Altogether, these data suggest that TLR4 plays a role in the regulation of murine folliculogenesis and in determining ovarian endowment. TLR4 deficiency may affect ovulation and pregnancy rates, potentially decreasing fertility, therefore the potential side effects of its blockade have to be carefully investigated.

Keywords

FertilityFollicleOvaryTLR4
Type
Research Article
Information
Zygote , Volume 30 , Issue 2 , April 2022 , pp. 227 - 233
Copyright
© The Author(s), 2021. Published by Cambridge University Press

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References

Anderson, RC, Newton, CL, Anderson, RA and Millar, RP (2018). Gonadotropins and their analogs: Current and potential clinical applications. Endocr Rev 39, 911–37.CrossRefGoogle ScholarPubMed
Atli, MO, Kose, M, Hitit, M, Kaya, MS and Bozkaya, F (2018). Expression patterns of Toll-like receptors in the ovine corpus luteum during the early pregnancy and prostaglandin F2α-induced luteolysis. Theriogenology 111, 25–33.Google ScholarPubMed
Brown, HM, Dunning, KR, Robker, RL, Boerboom, D, Pritchard, M, Lane, M and Russell, DL (2010). ADAMTS1 cleavage of versican mediates essential structural remodeling of the ovarian follicle and cumulus–oocyte matrix during ovulation in mice. Biol Reprod 83, 549–57.CrossRefGoogle ScholarPubMed
Byers, SL, Wiles, MV, Dunn, SL and Taft, RA (2012). Mouse estrous cycle identification tool and images. PLoS One 7, e35538.Google ScholarPubMed
Campos-Junior, PHA, Marinho Assuncao, CM, Carvalho, BC, Batista, RITP, Garcia, RMG and Viana, JHM (2012). Follicular populations, recruitment and atresia in the ovaries of different strains of mice. Reprod Biol 12, 41–55.CrossRefGoogle ScholarPubMed
Chin, PY, Dorian, CL, Hutchinson, MR, Olson, DM, Rice, KC, Moldenhauer, LM and Robertson, SA (2016). Novel Toll-like receptor-4 antagonist+-naloxone protects mice from inflammation-induced preterm birth. Sci Rep 6, 36112.Google ScholarPubMed
Conforti, A, Esteves, SC, Di Rella, F, Strina, I, De Rosa, P, Fiorenza, A, Zullo, F, De Placido, G and Alviggi, C (2019). The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: A systematic review and meta-analysis. Reprod Biol Endocrinol 17, 18.CrossRefGoogle ScholarPubMed
Ding, SQ, Li, Y, Zhou, ZG, Wang, C, Zhan, L and Zhou, B (2010). Toll-like receptor 4-mediated apoptosis of pancreatic cells in cerulein-induced acute pancreatitis in mice. Hepatobiliary Pancreat Dis Int 9, 645–50.Google ScholarPubMed
El-Zayat, SR, Sibaii, H and Mannaa, FA (2019). Toll-like receptors activation, signaling, and targeting: An overview. Bull Natl Res Centre 43, 187.Google Scholar
Eppig, JJ, Wigglesworth, K and Pendola, FL (2002). The mammalian oocyte orchestrates the rate of ovarian follicular development. Proc Natl Acad Sci USA 99, 2890–4.Google ScholarPubMed
Ernst, EH, Amoushahi, M, Sørensen, AS, Kragstrup, TW, Ernst, E and Lykke-Hartmann, K (2020). Distinct expression patterns of TLR transcripts in human oocytes and granulosa cells from primordial and primary follicles. J Reprod Immunol 140, 103125.Google ScholarPubMed
Gu, BX, Wang, X, Yin, BL, Guo, HB, Zhang, HL, Zhang, SD and Zhang, CL (2016). Abnormal expression of TLRs may play a role in lower embryo quality of women with polycystic ovary syndrome. System Biol Reprod Med 62, 353–8.CrossRefGoogle ScholarPubMed
Hoshino, K, Takeuchi, O, Kawai, T, Sanjo, H, Ogawa, T, Takeda, Y, Takeda, K and Akira, S (1999). Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the LPS gene product. J Immunol 162, 3749–52.Google ScholarPubMed
Hosseini, S, Dehghani-Mohammadabadi, M, Ghafarri Novin, M, Haji Molla Hoseini, M, Arefian, E, Mohammadi Yeganeh, S and Salehi, M (2017). Toll-like receptor4 as a modulator of fertilization and subsequent pre-implantation development following in vitro maturation in mice. Am J Reprod Immunol 78, e12720.Google ScholarPubMed
Ji, Y, Sun, S, Shrestha, N, Darragh, LB, Shirakawa, J, Xing, Y, He, Y, Carboneau, BA, Kim, H, An, D, Ma, M, Oberholzer, J, Soleimanpour, SA, Gannon, M, Liu, C, Naji, A, Kulkarni, RN, Wang, Y, Kersten, S and Qi, L (2019). Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity. Nat Immunol 20, 677–86.Google ScholarPubMed
Jiang, S, Li, X, Hess, NJ, Guan, Y and Tapping, RI (2016). TLR10 is a negative regulator of both MyD88-dependent and -independent TLR signaling. J Immunol 196, 3834–41.Google ScholarPubMed
Jones, ASK and Shikanov, A (2019). Follicle development as an orchestrated signaling network in a 3D organoid. J Biol Eng 13, 2.CrossRefGoogle Scholar
Jung, DY, Lee, H, Jung, BY, Ock, J, Lee, MS, Lee, WH and Suk, K (2005). TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia: A critical role of IFN-β as a decision maker. J Immunol 174, 6467–76.CrossRefGoogle Scholar
Kashani, B, Zandi, Z, Bashash, D, Zaghal, A, Momeny, M, Poursani, EM, Pourbagheri-Sigaroodi, A, Mousavi, SA and Ghaffari, SH (2020). Small molecule inhibitor of TLR4 inhibits ovarian cancer cell proliferation: New insight into the anticancer effect of TAK-242 (resatorvid). Cancer Chemother Pharmacol 85, 47–59.Google Scholar
Li, C, Che, LH, Ji, TF, Shi, L and Yu, JL (2017). Effects of the TLR4 signaling pathway on apoptosis of neuronal cells in diabetes mellitus complicated with cerebral infarction in a rat model. Sci Rep 7, 43834.Google ScholarPubMed
Li, Z, Block, MS, Vierkant, RA, Fogarty, ZC, Winham, SJ, Visscher, DW, Kalli, KR, Wang, C and Goode, EL (2016). The inflammatory microenvironment in epithelial ovarian cancer: A role for TLR4 and MyD88 and related proteins. Tumour Biol 37, 13279–86.Google ScholarPubMed
Liu, Z, Shimada, M and Richards, JS (2008). The involvement of the toll-like receptor family in ovulation. J Assist Reprod Genet 25, 223–8.Google ScholarPubMed
Luo, J, McGinnis, LK and Kinsey, WH (2010). Role of Fyn kinase in oocyte developmental potential. Reprod Fertil Dev 22, 966–76.CrossRefGoogle ScholarPubMed
Lupi, LA, Cucielo, MS, Silveira, HS, Gaiotte, LB, Cesário, RC, Seiva, FRF and de Almeida Chuffa, LG (2020). The role of Toll-like receptor 4 signaling pathway in ovarian, cervical, and endometrial cancers. Life Sci 247, 117435.Google ScholarPubMed
Mohamed, NE, Hay, T, Reed, KR, Smalley, MJ and Clarke, AR (2019). APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression. BMC Cancer 19, 677.CrossRefGoogle ScholarPubMed
Monniaux, D, Clément, F, Dalbiès-Tran, R, Estienne, A, Fabre, S, Mansanet, C and Monget, P (2014). The ovarian reserve of primordial follicles and the dynamic reserve of antral growing follicles: What is the link? Biol Reprod 90, 85.Google ScholarPubMed
Pereira, LAAC, Nascimento, BR, Jorge, EC, Segatelli, TM, Coutinho, LL, Viana, JHM and Campos-Junior, PHA (2020). Vitrification leads to transcriptomic modifications of mice ovaries that do not affect folliculogenesis progression. Reprod Biol 20, 264–72.CrossRefGoogle Scholar
Piprek, RP (Ed.) (2016). Mechanisms of Cell Differentiation in Gonad Development. Springer International Publishing.Google Scholar
Santos, AGA, Pereira, LAAC, Viana, JHM, Russo, RC and Campos-Junior, PHA (2020). The CC-chemokine receptor 2 is involved in the control of ovarian folliculogenesis and fertility lifespan in mice. J Reprod Immunol 141, 103174.CrossRefGoogle ScholarPubMed
Schjenken, JE, Glynn, DJ, Sharkey, DJ and Robertson, SA (2015). TLR4 signaling is a major mediator of the female tract response to seminal fluid in mice. Biol Reprod 93, 68.Google ScholarPubMed
Shimada, M, Hernandez-Gonzalez, I, Gonzalez-Robanya, I and Richards, JS (2006). Induced expression of pattern recognition receptors in cumulus oocyte complexes: Novel evidence for innate immune-like functions during ovulation. Mol Endocrinol 20, 3228–39.CrossRefGoogle ScholarPubMed
Shimada, M, Yanai, Y, Okazaki, T, Noma, N, Kawashima, I, Mori, T and Richards, JS (2008). 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 135, 2001–11.Google ScholarPubMed
Sun, XL, Zhang, J, Fan, Y, Ding, JH, Sha, JH and Hu, G (2009). Aquaporin-4 deficiency induces subfertility in female mice. Fertil Steril 92, 1736–43.CrossRefGoogle ScholarPubMed
Uri-Belapolsky, S, Shaish, A, Eliyahu, E, Grossman, H, Levi, M, Chuderland, D, Ninio-Many, L, Hasky, N, Shashar, D, Almog, T, Kandel-Kfir, M, Harats, D, Shalgi, R and Kamari, Y (2014). Interleukin-1 deficiency prolongs ovarian lifespan in mice. Proc Natl Acad Sci USA 111, 12492–7.Google ScholarPubMed
Vaure, C and Liu, Y (2014). A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol 5, 316.Google ScholarPubMed
Vidya, MK, Kumar, VG, Sejian, V, Bagath, M, Krishnan, G and Bhatta, R (2018). Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol 37, 20–36.CrossRefGoogle ScholarPubMed
Wahid, HH, Dorian, CL, Chin, PY, Hutchinson, MR, Rice, KC, Olson, DM, Moldenhauer, LM and Robertson, SA (2015). Toll-like receptor 4 is an essential upstream regulator of on-time parturition and perinatal viability in mice. Endocrinology 156, 3828–41.CrossRefGoogle ScholarPubMed
Walker, MP, Tian, L and Matera, AG (2009). Reduced viability, fertility and fecundity in mice lacking the Cajal body marker protein, coilin. PLoS One 4, e6171.Google ScholarPubMed
Yang, H, Pang, H and Miao, C (2018). Ovarian IL-1α and IL-1β levels are associated with primary ovarian insufficiency. Int J Clin Exp Pathol 11, 4711–7.Google ScholarPubMed