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Hemoglobin-induced continuous activation of macrophages in endometriotic cysts: a potential mechanism of endometriosis development and carcinogenesis

Abstract

Endometriosis is a chronic inflammatory disease. Endometriotic cysts contain hemoglobin (Hb) and infiltrated macrophages, indicating that the metabolism of Hb by macrophages may play an important role in the inflammation of endometriotic cysts. In this study, we investigated the distribution of immune cells and CD163 (Hb receptor)-positive cells in the endometriotic cyst wall using immunohistochemistry. We also examined the role of macrophage activation by Hb on the pathogenesis of endometriotic cysts by measuring the cytokine concentration in the cystic fluids and macrophage-culture supernatant using ELISA. Macrophages were the most prominent immune cells observed in the endometriotic cysts and were differentially distributed in the different histological areas of the cyst wall. The localization of CD163-positive macrophages was restricted to the hemorrhagic and outer areas in the cyst wall. High concentrations of IL-6 and CCL2 were found in the cystic fluids, and inflammatory cytokines (IL-6, TNF-α, and CCL2) were secreted from macrophages on stimulation by Hb. IL-6 is a promotional factor for endometriotic stromal cells and ovarian clear cell carcinoma, the most common histological subtype of endometriosis-related ovarian cancer, hence, the continuous activation of macrophages by Hb could be a potential mechanism underlying endometriosis development and carcinogenesis.

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References

  1. Zondervan KT, Becker CM, Missmer SA (2020) Endometriosis. N Engl J Med 382:1244–1256

    CAS  Article  Google Scholar 

  2. Irving JA, Clement PB (2019) Disease of the peritoneum. In: Kurman RJ, Ronnett BM, Ellenson L (eds) Blaustein’s pathology of the female genital tract, 7th edn. Springer Nature Switzerland AG, Switzerland, pp 771–840

    Chapter  Google Scholar 

  3. Nisolle M, Donnez J (1997) Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of rectovaginal septum are three different entities. Fertil Steril 68:585–596

    CAS  Article  Google Scholar 

  4. Adghari S, Valizadeh A, Aghebati-Maleki L, Nouri M, Yousefi M (2018) Endometriosis: perspective, lights, and shadows of etiology. Biomed Pharmacother 106:163–174

    Article  Google Scholar 

  5. Vinatier D, Dufour P, Oosterlynck D (1996) Immunological aspects of endometriosis. Hum Reprod Update 2:371–384

    CAS  Article  Google Scholar 

  6. Oral E, Olive DL, Arici A (1996) The peritoneal environment in endometriosis. Hum Reprod Update 2:385–398

    CAS  Article  Google Scholar 

  7. Kobayashi H, Higashiura Y, Shigetomi H, Kajihara H (2014) Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation. Mol Med Rep 9:9–15

    CAS  Article  Google Scholar 

  8. Sanchez AM, Vigano P, Somigliana E, Panina-Bordignon P, Vercellini P, Candiani M (2014) The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary. Hum Reprod Update 20:217–230

    CAS  Article  Google Scholar 

  9. Fukumatsu Y, Katabuchi H, Miyamura S, Matsuura K, Okamura H, Naito M, Takahashi K (1992) Activated macrophages in the peritoneal fluid of women with endometriosis: examination of the intracytoplasmic localization of endogenous peroxidase and interleukin-1. Acta Obstet Gynaecol Jpn 44:529–536

    CAS  Google Scholar 

  10. Koyama N, Matsuura K, Okamura H (1993) Cytokines in the peritoneal fluid of patients with endometriosis. Int J Gynecol Obstet 43:45–50

    CAS  Article  Google Scholar 

  11. Yih S, Katabuchi H, Araki M, Matsuura K, Takeya M, Takahashi K, Okamura H (2001) Expression of monocyte chemoattractant protein-1in peritoneal endometriotic cells. Virchows Arch 438:70–77

    CAS  Article  Google Scholar 

  12. Okamura H, Katabuchi H, Kanzaki H (2002) Macrophages in reproductive biology. In: Burke B, Lewis CE (eds) The macrophage, 2nd edn. Oxford University Press, New York, pp 549–576

    Google Scholar 

  13. Khan KN, Kitajima M, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H (2008) Immunopathogenesis of pelvic endometriosis: role of hepatocyte growth factor, macrophages and ovarian steroids. Am J Reprod Immunol 60:383–404

    CAS  Article  Google Scholar 

  14. Itoh F, Komohara Y, Takaishi K, Honda R, Tashiro H, Kyo S, Katabuchi H, Takeya M (2013) Possible involvement of signal transducer and activator of transcription-3 in cell-cell interactions of peritoneal macrophages and endometrial stromal cells in human endometriosis. Fertil Steril 99:1705–1713

    CAS  Article  Google Scholar 

  15. Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R, Tayade C (2015) Pathophysiology and immune dysfunction in endometriosis. Biomed Res Int 2015:795976

    PubMed  PubMed Central  Google Scholar 

  16. Riccio LGC, Santulli P, Marcellin L, Abrão MS, Batteux F, Chapron C (2018) Immunology of endometriosis. Best Pract Res Clin Obstet Gynaecol 50:39–49

    Article  Google Scholar 

  17. Badawy SZ, Cuenca V, Kumar S, Holland J (1998) Effects of chocolate cyst fluid on endometrioma cell growth in culture. Fertil Steril 70:827–830

    CAS  Article  Google Scholar 

  18. Fasciani A, D’Ambrogio G, Bocci G, Luisi S, Artini PG, Genazzani AR (2001) Vascular endothelial growth factor and interleukin-8 in ovarian cystic pathology. Fertil Steril 75:1218–1221

    CAS  Article  Google Scholar 

  19. Daraï E, Detchev R, Hugol D, Quang NT (2003) Serum and cyst fluid levels of interleukin (IL)-6, IL-8 and tumour necrosis factor-alpha in women with endometriomas and benign and malignant cystic ovarian tumours. Hum Reprod 18:1681–1685

    Article  Google Scholar 

  20. Velasco I, Aciéna P, Campos A, Aciéna MI, Ruiz-Maciá E (2010) Interleukin-6 and other soluble factors in peritoneal fluid and endometriomas and their relation to pain and aromatase expression. J Reprod Immunol 84:199–205

    CAS  Article  Google Scholar 

  21. Iba Y, Harada T, Horie S, Deura I, Iwabe T, Terakawa N (2004) Lipopolysaccharide-promoted proliferation of endometriotic stromal cells via induction of tumor necrosis factor and interleukin-8 expression. Fertil Steril 82:1036–1042

    CAS  Article  Google Scholar 

  22. Suen JL, Chang Y, Chiu PR, Hsieh TH, His E, Chen YC, Chen YF, Tsai Serum EM (2014) Level of IL-10 is increased in patients with endometriosis, and IL-10 promotes the growth of lesions in a murine model. Am J Pathol 184:464–471

    CAS  Article  Google Scholar 

  23. Miller JE, Ahn SH, Monsanto SP, Khalaj K, Koti M, Tayade C (2017) Implications of immune dysfunction on endometriosis associated infertility. Oncotarget 8:7138–7147

    Article  Google Scholar 

  24. Munksgaard PS, Blaakaer J (2012) The association between endometriosis and ovarian cancer: a review of histological, genetic and molecular alterations. Gynecol Oncol 124:164–169

    CAS  Article  Google Scholar 

  25. Pavone ME, Lyttle BM (2015) Endometriosis and ovarian cancer: links, risks, and challenges faced. Int J Womens Health 7:663–672

    Article  Google Scholar 

  26. Yanaihara N, Hirata Y, Yamaguchi N, Noguchi Y, Saito M, Nagata C, Takakura S, Yamada K, Okamoto A (2016) Antitumor effects of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling pathway inhibition in clear cell carcinoma of the ovary. Mol Carcinog 55:832–841

    CAS  Article  Google Scholar 

  27. Nanda A, Thangapandi K, Banerjee P, Dutta M, Wangdi T, Sharma P, Chaudhury K, Jana SK (2020) Cytokines, angiogenesis, and extracellular matrix degradation are augmented by oxidative stress in endometriosis. Ann Lab Med 40:390–397

    Article  Google Scholar 

  28. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK (2001) Identification of the haemoglobin scavenger receptor. Nature 409:198–201

    CAS  Article  Google Scholar 

  29. Bacci M, Capobianco A, Monno A, Cottone L, Puppo FD, Camisa B, Mariani M, Brignole C, Ponzoni M, Ferrari S, Panina-Bordignon P, Manfredi AA, Rovere-Querini P (2009) Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease. Am J Pathol 175:547–556

    CAS  Article  Google Scholar 

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Acknowledgements

We thank Ms. Hikaru Sakamato, Mr. Takuto Tsuru, Ms. Ayaka Nakashima, Mr. Takenobu Nakagawa, and all members of the Department of Cell Pathology and the Department of Obstetrics and Gynecology, Kumamoto University for their technical assistance. We would like to thank Editage (www.editage.com) for English language editing.

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Correspondence to Hidetaka Katabuchi.

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Kusunoki, M., Fujiwara, Y., Komohara, Y. et al. Hemoglobin-induced continuous activation of macrophages in endometriotic cysts: a potential mechanism of endometriosis development and carcinogenesis. Med Mol Morphol 54, 122–132 (2021). https://doi.org/10.1007/s00795-020-00272-4

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  • DOI: https://doi.org/10.1007/s00795-020-00272-4

Keywords

  • Endometriotic cyst
  • Inflammation
  • Macrophage
  • Hemoglobin
  • CD163