Skip to main content
SpringerLink
Log in

Increased expression of NLRP3 inflammasome components in granulosa cells and follicular fluid interleukin(IL)-1beta and IL-18 levels in fresh IVF/ICSI cycles in women with endometriosis

  • Reproductive physiology and disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

The inflammasomes are a family of recently described multi-protein cytoplasmic sensors that orchestrate the inflammatory response and participate in a variety of inflammatory conditions. We hypothesized that the activation of pyrin domain‑containing protein 3 (NLRP3) inflammasome by granulosa cells (hGCs) may be activated in women with endometriosis and influence oocyte maturation and IVF outcomes. We performed a cross-sectional study to investigate the NLRP3 inflammasome status in follicular fluid (FF) and in hGCs from 44 women undergoing controlled ovarian stimulation for IVF/ICSI. Study subjects were divided into two groups according to the infertility etiology: group with tubal or male factor (control, n = 22) vs. group with endometriosis (n = 22). The FF IL-1beta and IL-18 levels in the endometriosis group were significantly higher than those in the non-endometriosis group, i.e., 5010 pg/mL and 2738 pg/mL, respectively (p < 0.05). No correlation was found between clinical pregnancy and live birth rate and analyzed inflammasome component levels (p > 0.05). In addition, the hGCs from endometriosis women demonstrated high expression of NLRP3 inflammasome at both protein and mRNA levels. Higher expression of inflammasome components within the ovary compartment may result from the exaggerated inflammatory state associated with endometriosis and thus impact the fertility of these women.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials. The data that support the findings of this study are available from the corresponding authors, Bruno Fonseca or Irene Rebelo, upon reasonable request.

References

  1. Ahn SH, Khalaj K, Young SL, Lessey BA, Koti M, Tayade C. Immune-inflammation gene signatures in endometriosis patients. Fertil Steril. 2016;106(6):1420. https://doi.org/10.1016/j.fertnstert.2016.07.005.

    Article  CAS  Google Scholar 

  2. Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R, Tayade C. Pathophysiology and immune dysfunction in endometriosis. Biomed Res Int. 2015;2015:795976. https://doi.org/10.1155/2015/795976.

    Article  CAS  Google Scholar 

  3. Ashrafi M, Sadatmahalleh SJ, Akhoond MR, Talebi M. Evaluation of risk factors associated with endometriosis in infertile women. Intl J Fertil Steril. 2016;10(1):11–21.

    CAS  Google Scholar 

  4. Barbakadze L, Kristesashvili J, Khonelidze N, Tsagareishvili G. The correlations of anti-mullerian hormone follicle-stimulating hormone and antral follicle count in different age groups of infertile women. Int J Fertil Steril. 2015;8(4):393–8. https://doi.org/10.22074/ijfs.2015.4179.

    Article  CAS  Google Scholar 

  5. Bulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet. 2010;27(8):441–7. https://doi.org/10.1007/s10815-010-9436-1.

    Article  Google Scholar 

  6. D’Ippolito S, Tersigni C, Marana R, Di Nicuolo F, Gaglione R, Rossi ED, Castellani R, Scambia G, Di Simone N. Inflammosome in the human endometrium: further step in the evaluation of the “maternal side.” Fertil Steril. 2016;105(1):111-118 e111-114. https://doi.org/10.1016/j.fertnstert.2015.09.027.

    Article  CAS  Google Scholar 

  7. Eisenberg VH, Weil C, Chodick G, Shalev V. Epidemiology of endometriosis: a large population-based database study from a healthcare provider with 2 million members. BJOG. 2018;125(1):55–62. https://doi.org/10.1111/1471-0528.14711.

    Article  CAS  Google Scholar 

  8. Fonseca BM, Cunha SC, Goncalves D, Mendes A, Braga J, Correia-da-Silva G, Teixeira NA. Decidual NK cell-derived conditioned medium from miscarriages affects endometrial stromal cell decidualisation: endocannabinoid anandamide and tumour necrosis factor-alpha crosstalk. Hum Reprod. 2020;35(2):265–74. https://doi.org/10.1093/humrep/dez260.

    Article  CAS  Google Scholar 

  9. Fonseca BM, Moreira-Pinto B, Costa L, Felgueira E, Oliveira P, Rebelo I. Concentrations of the endocannabinoid N-arachidonoylethanolamine in the follicular fluid of women with endometriosis: the role of M1 polarised macrophages. Reprod Fertil Dev. 2021;33(4):270–8. https://doi.org/10.1071/RD20247.

    Article  CAS  Google Scholar 

  10. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21(7):677–87. https://doi.org/10.1038/nm.3893.

    Article  CAS  Google Scholar 

  11. Huang FY, Cao J, Liu QH, Zou Y, Li HY, Yin TF. MAPK/ERK signal pathway involved expression of COX-2 and VEGF by IL-1 beta induced in human endometriosis stromal cells in vitro. Intl J Clin Exp Pathol. 2013;6(10):2129–36.

    Google Scholar 

  12. Jenabi E, Khazaei S, Veisani Y. The association between body mass index and the risk of endometriosis: a meta-analysis. J Endometriosis Pelvic Pain Disord. 2019;11(2):55–61. https://doi.org/10.1177/2284026519832814.

    Article  Google Scholar 

  13. Kol S, BenShlomo I, Ruutiainen K, Ando M, DaviesHill TM, Rohan RM, Simpson IA, Adashi EY. The midcycle increase in ovarian glucose uptake is associated with enhanced expression of glucose transporter 3 - possible role for interleukin-1, a putative intermediary in the ovulatory process. J Clin Investig. 1997;99(9):2274–83. https://doi.org/10.1172/Jci119403.

    Article  CAS  Google Scholar 

  14. Kolanska K, Alijotas-Reig J, Cohen J, Cheloufi M, Selleret L, d’Argent E, Kayem G, Valverde EE, Fain O, Bornes M, Darai E, Mekinian A. Endometriosis with infertility: a comprehensive review on the role of immune deregulation and immunomodulation therapy. Am J Reprod Immunol. 2021;85(3):e13384. https://doi.org/10.1111/aji.13384.

    Article  CAS  Google Scholar 

  15. Koninckx PR, Ussia A, Adamyan L, Tahlak M, Keckstein J, Wattiez A, Martin DC. The epidemiology of endometriosis is poorly known as the pathophysiology and diagnosis are unclear. Best Pract Res Clin Obstet Gynaecol. 2021;71:14–26. https://doi.org/10.1016/j.bpobgyn.2020.08.005.

    Article  Google Scholar 

  16. Liu Y, Liu H, Li Z, Fan H, Yan X, Liu X, Xuan J, Feng D, Wei X. The release of peripheral immune inflammatory cytokines promote an inflammatory cascade in PCOS patients via altering the follicular microenvironment. Front Immunol. 2021;12:685724. https://doi.org/10.3389/fimmu.2021.685724.

    Article  CAS  Google Scholar 

  17. Lliberos C, Liew SH, Mansell A, Hutt KJ. The inflammasome contributes to depletion of the ovarian reserve during aging in mice. Front Cell Dev Biol. 2020;8:628473. https://doi.org/10.3389/fcell.2020.628473.

    Article  Google Scholar 

  18. Lu M, Ma F, Xiao J, Yang L, Li N, Chen D. NLRP3 inflammasome as the potential target mechanism and therapy in recurrent spontaneous abortions. Mol Med Rep. 2019;19(3):1935–41. https://doi.org/10.3892/mmr.2019.9829.

    Article  CAS  Google Scholar 

  19. Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. Mitochondrial control of inflammation. Nat Rev Immunol. 2022. https://doi.org/10.1038/s41577-022-00760-x.

    Article  Google Scholar 

  20. Matias ML, Romao M, Weel IC, Ribeiro VR, Nunes PR, Borges VT, Araujo JP Jr, Peracoli JC, de Oliveira L, Peracoli MT. Endogenous and uric acid-induced activation of NLRP3 inflammasome in pregnant women with preeclampsia. PLoS ONE. 2015;10(6):e0129095. https://doi.org/10.1371/journal.pone.0129095.

    Article  CAS  Google Scholar 

  21. Murakami M, Osuka S, Muraoka A, Hayashi S, Bayasula Y, Kasahara, Sonehara R, Hariyama Y, Shinjo K, Tanaka H, Miyake N, Yoshita S, Nakanishi N, Nakamura T, Goto M, Kajiyama H. Effectiveness of NLRP3 inhibitor as a non-hormonal treatment for ovarian endometriosis. Reprod Biol Endocrinol. 2022;20(1):58. https://doi.org/10.1186/s12958-022-00924-3.

    Article  CAS  Google Scholar 

  22. Navarro-Pando JM, Alcocer-Gomez E, Castejon-Vega B, Navarro-Villaran E, Condes-Hervas M, Mundi-Roldan M, Muntande J, Perez-Pulido AJ, Bullon P, Wang C, Hoffman HM, Sanz A, Mbalaviele G, Ryffel B, Cordero MD. Inhibition of the NLRP3 inflammasome prevents ovarian aging. Sci Adv. 2021;7(1):eabc7409. https://doi.org/10.1126/sciadv.abc7409.

    Article  CAS  Google Scholar 

  23. Riera MF, Meroni SB, Gomez GE, Schteingart HF, Pellizzari EH, Cigorraga SB. Regulation of lactate production by FSH, iL1beta, and TNFalpha in rat Sertoli cells. Gen Comp Endocrinol. 2001;122(1):88–97. https://doi.org/10.1006/gcen.2001.7619.

    Article  CAS  Google Scholar 

  24. Rostamtabar M, Esmaeilzadeh S, Karkhah A, Amiri M, Rahmani A, Bakouei F, Nouri HR. Elevated expression of IL-18 but not IL-1 beta gene is associated with NALP3 and AIM2 inflammasome in Polycystic Ovary Syndrome. Gene. 2020;731:144352. https://doi.org/10.1016/j.gene.2020.144352.

    Article  CAS  Google Scholar 

  25. Voet, S., Srinivasan, S., Lamkanfi, M., & van Loo, G. (2019). Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med, 11(6). https://doi.org/10.15252/emmm.201810248

  26. Xu Q, Zhao B, Ye Y, Li Y, Zhang Y, Xiong X, Gu L. Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke. J Neuroinflammation. 2021;18(1):123. https://doi.org/10.1186/s12974-021-02137-8.

    Article  CAS  Google Scholar 

  27. Yang Y, Wang H, Kouadir M, Song H, Shi F. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis. 2019;10(2):128. https://doi.org/10.1038/s41419-019-1413-8.

    Article  Google Scholar 

  28. Zhang Y, Yang W, Li W, Zhao Y. NLRP3 inflammasome: checkpoint connecting innate and adaptive immunity in autoimmune diseases. Front Immunol. 2021;12:732933. https://doi.org/10.3389/fimmu.2021.732933.

    Article  CAS  Google Scholar 

  29. Zhao J, Ma W, Chen WZ, Gao J, Li CL, Tong YH, Zhou Q, Zhao XL, Wang MH, Xiao H, Jin YR. AEG-1 aggravates inflammation via promoting NALP3 inflammasome formation in murine endometriosis lesions. Animal Cells and Systems. 2019;23(6):407–13. https://doi.org/10.1080/19768354.2019.1691052.

    Article  CAS  Google Scholar 

  30. Zhao S, Chen F, Yin Q, Wang D, Han W, Zhang Y. Reactive oxygen species interact with NLRP3 inflammasomes and are involved in the inflammation of sepsis: from mechanism to treatment of progression. Front Physiol. 2020;11:571810. https://doi.org/10.3389/fphys.2020.571810.

    Article  Google Scholar 

  31. Zheng D, Liwinski T, Elinav E. Inflammasome activation and regulation: toward a better understanding of complex mechanisms. Cell Discov. 2020;6:36. https://doi.org/10.1038/s41421-020-0167-x.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the whole staff from the CHVNG/E for their assistance. This work is financed by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB.

Funding

This work was financially supported by FCT—Fundação para a Ciência e a Tecnologia, I.P., in the framework of the project PTDC/MEC-OUT/28931/2017.

Author information

Authors and Affiliations

  1. UCIBIO-REQUIMTE, Laboratório de Bioquímica, Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade Do Porto, Porto, Portugal

    Bruno M. Fonseca, Beatriz Pinto, Lia Costa & Irene Rebelo

  2. Associate Laboratory i4HB - Institute for Health and Bioeconomy, Laboratório de Bioquímica, Departamento de Ciências Biológicas, Faculdade de Farmácia da Universidade Do Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313, Porto, Portugal

    Bruno M. Fonseca, Beatriz Pinto, Lia Costa & Irene Rebelo

  3. Unidade de Medicina da Reprodução Dra. Ingeborg Chaves, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal

    Lia Costa & Eduarda Felgueira

Authors
  1. Bruno M. Fonseca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Beatriz Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lia Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eduarda Felgueira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Irene Rebelo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed substantially to this work. The authors collectively developed the original concept of this study. BMF wrote the manuscript. IR revised it critically. Data collection and analysis were performed by BMF; BP, EF, and LC helped with the collection of follicular fluid and contributed to the data analysis and study preparation and statistical analysis by BMF. The authors contributed to critical discussion and reviewed and approved the final version of the manuscript for submission.

Corresponding authors

Correspondence to Bruno M. Fonseca or Irene Rebelo.

Ethics declarations

Ethics approval

This study was approved by the Ethics Committee of Centro Hospitalar de Vila Nova de Gaia/Espinho) and by the National Data Protection Commission (authorization number 526/2017). Informed consent was signed by the patients.

Conflicts of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 14 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fonseca, B.M., Pinto, B., Costa, L. et al. Increased expression of NLRP3 inflammasome components in granulosa cells and follicular fluid interleukin(IL)-1beta and IL-18 levels in fresh IVF/ICSI cycles in women with endometriosis. J Assist Reprod Genet 40, 191–199 (2023). https://doi.org/10.1007/s10815-022-02662-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-022-02662-2

Keywords

Search

Navigation