Downregulation of pattern recognition receptors on macrophages involved in aggravation of endometriosis

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Abstract

PROBLEM: In women of reproductive age, endometriosis may contribute to dysmenorrhea, chronic pelvic pain, dyspareunia, infertility, adenomyosis, and endometrial ovarian cyst (EOC). Recent studies have shown that chronic inflammation occurs in the pelvis of endometriosis patients and that this inflammation is exacerbated by immunosuppression, leading to survival endometrial debris. However, the detailed immunological mechanisms underlying the aggravation of inflammation and immunosuppression in endometriosis patients remain unclear. METHOD OF STUDY: We investigate the alarmins (high-mobility group box-1, IL-33, IL-1α, and S100B protein), proinflammatory cytokines (IL-6 and IL-1β), and immune cells (CD8+ T cells, CD4+ T cells, natural killer cells, natural killer T cells, dendritic cells, and macrophages) in peritoneal fluid of patients with EOC using enzyme-linked immunosorbent assay, electrochemiluminescence, and flow cytometry. Then, we analyzed the correlation between these factors and the aggravating indicators of endometriosis, tumor size and revised American Society for Reproductive Medicine (r-ASRM) score. RESULTS: Unexpectedly, there was no correlation between each alarmin level and aggravating indicators. However, the expression of pattern recognition receptors, toll-like receptor 4, and receptor of advanced glycation end-products on macrophages was inversely correlated with aggravating indicators. CONCLUSIONS: The aggravation of endometriosis is associated with a decrease in alarmin receptors but not alarmin levels. Investigation of innate immune systems, such as alarmins and their receptors, may help elucidate new mechanisms of endometriosis.
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Abstract

Problem In women of reproductive age, endometriosis may contribute to dysmenorrhea, chronic pelvic pain, dyspareunia, infertility, adenomyosis, and endometrial ovarian cyst (EOC). Recent studies have shown that chronic inflammation occurs in the pelvis of endometriosis patients and that this inflammation is exacerbated by immunosuppression, leading to survival endometrial debris. However, the detailed immunological mechanisms underlying the aggravation of inflammation and immunosuppression in endometriosis patients remain unclear.

Method

of Study We investigate the alarmins (high-mobility group box-1, IL-33, IL-1α, and S100B protein), proinflammatory cytokines (IL-6 and IL-1β), and immune cells (CD8+ T cells, CD4+ T cells, natural killer cells, natural killer T cells, dendritic cells, and macrophages) in peritoneal fluid of patients with EOC using enzyme-linked immunosorbent assay, electrochemiluminescence, and flow cytometry. Then, we analyzed the correlation between these factors and the aggravating indicators of endometriosis, tumor size and revised American Society for Reproductive Medicine (r-ASRM) score.

Results

Unexpectedly, there was no correlation between each alarmin level and aggravating indicators. However, the expression of pattern recognition receptors, toll-like receptor 4, and receptor of advanced glycation end-products on macrophages was inversely correlated with aggravating indicators.

Conclusions

The aggravation of endometriosis is associated with a decrease in alarmin receptors but not alarmin levels. Investigation of innate immune systems, such as alarmins and their receptors, may help elucidate new mechanisms of endometriosis. CONFLICT OF INTEREST STATEMENT There are no conflicts of interest to declare. DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author, [Y. N.], upon reasonable request. Supporting Information | Filename | Description | |---|---| | aji13812-sup-0001-FigureS1-S6.docx50.7 MB | Supporting Information | | aji13812-sup-0002-TableS1.docx17.7 KB | Supporting Information | | aji13812-sup-0003-TableS2.docx14.1 KB | Supporting Information | | aji13812-sup-0004-TableS3.docx14.4 KB | Supporting Information | | aji13812-sup-0005-FigureS1.tif8.3 MB | Supporting Information | | aji13812-sup-0006-FigureS2-1.tif5.8 MB | Supporting Information | | aji13812-sup-0007-FigureS2-2.tif6.8 MB | Supporting Information | | aji13812-sup-0008-FigureS3-1.tif3.9 MB | Supporting Information | | aji13812-sup-0009-FigureS3-2.tif6 MB | Supporting Information | | aji13812-sup-0010-FigureS4.tif4.9 MB | Supporting Information | | aji13812-sup-0011-FigureS5.tif7.9 MB | Supporting Information | | aji13812-sup-0012-FigureS6.tif7 MB | Supporting Information | Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

References

- 1Brosens I, Brosens JJ, Fusi L, Al-Sabbagh M, Kuroda K, Benagiano G. Risks of adverse pregnancy outcome in endometriosis. Fertil Steril. 2012; 98(1): 30-35. - 2Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927; 3(2): 93-110.143. - 3Kobayashi H, Higashiura Y, Shigetomi H, Kajihara H. Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation (Review). Mol Med Rep. 2014; 9(1): 9-15. - 4Khan KN, Fujishita A, Hiraki K, et al. Bacterial contamination hypothesis: a new concept in endometriosis. Reprod Med Biol. 2018; 17(2): 125-133. - 5Khan KN, Kitajima M, Hiraki K, et al. Toll-like receptors in innate immunity: role of bacterial endotoxin and toll-like receptor 4 in endometrium and endometriosis. Gynecol Obstet Invest. 2009; 68(1): 40-52. - 6Moghaddam MZ, Ansariniya H, Seifati SM, Zare F, Fesahat F. Immunopathogenesis of endometriosis; an overview of the role of innate and adaptive immune cells and their mediators. Am J Reprod Immunol. 2022; 87(5):e13537. - 7Freigang S, Ampenberger F, Weiss A, et al. Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1alpha and sterile vascular inflammation in atherosclerosis. Nat Immunol. 2013; 14(10): 1045-1053. - 8Tang SCW, Yiu WH. Innate immunity in diabetic kidney disease. Nat Rev Nephrol. 2020. - 9Mossman BT, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med. 1998; 157(5): 1666-1680. Pt 1. - 10Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420(6917): 860-867. - 11Rubartelli A, Lotze MT. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. 2007; 28(10): 429-436. - 12Tsung A, Tohme S, Billiar TR. High-mobility group box-1 in sterile inflammation. J Intern Med. 2014; 276(5): 425-443. - 13Medzhitov R. Decoding the patterns of self and nonself by the innate immune system. Science. 2002; 296(5566): 298-300. - 14Venereau E, Schiraldi M, Uguccioni M, Bianchi ME. HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol Immunol. 2013; 55(1): 76-82. - 15Lukens JR, Gross JM, Kanneganti TD. IL-1 family cytokines trigger sterile inflammatory disease. Front Immunol. 2012; 3: 315. - 16Hofmann MA, Drury S, Fu C, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999; 97(7): 889-901. - 17Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010; 10(2): 103-110. - 18Kajihara H, Yamada Y, Kanayama S, et al. New insights into the pathophysiology of endometriosis: from chronic inflammation to danger signal. Gynaecol Endocrino. 2011; 27(2): 73-79. - 19Nadeau-Vallée M, Obari D, Palacios J, et al. Sterile inflammation and pregnancy complications: a review. Reproduction. 2016; 152(6): R277-R292. - 20Kato M, Negishi Y, Shima Y, Kuwabara Y, Morita R, Takeshita T. Inappropriate activation of invariant natural killer T cells and antigen-presenting cells with the elevation of HMGB1 in preterm births without acute chorioamnionitis. Am J Reprod Immunol. 2020:e13330. - 21Ikeda M, Negishi Y, Akira S, Morita R, Takeshita T. Inflammation related to high-mobility group box-1 in endometrial ovarian cyst. J Reprod Immunol. 2021; 145:103292. - 22Nguyen H, Syed V. Progesterone inhibits growth and induces apoptosis in cancer cells through modulation of reactive oxygen species. Gynaecol Endocrino. 2011; 27(10): 830-836. - 23Young VJ, Brown JK, Saunders PT, Horne AW. The role of the peritoneum in the pathogenesis of endometriosis. Hum Reprod Update. 2013; 19(5): 558-569. - 24Capobianco A, Rovere-Querini P. Endometriosis, a disease of the macrophage. Front Immunol. 2013; 4: 9. - 25Chuang PC, Wu MH, Shoji Y, Tsai SJ. Downregulation of CD36 results in reduced phagocytic ability of peritoneal macrophages of women with endometriosis. J Pathol. 2009; 219(2): 232-241. - 26Mills CD. Macrophage arginine metabolism to ornithine/urea or nitric oxide/citrulline: a life or death issue. Crit Rev Immunol. 2001; 21(5): 399-425. - 27Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000; 164(12): 6166-6173. - 28Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013; 496(7446): 445-455. - 29Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004; 25(12): 677-686. - 30Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009; 27: 451-483. - 31Bacci M, Capobianco A, Monno A, et al. 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. 2009; 175(2): 547-556. - 32Ono Y, Yoshino O, Hiraoka T, et al. IL-33 exacerbates endometriotic lesions via polarizing peritoneal macrophages to M2 subtype. Reprod Sci. 2020; 27(3): 869-876. - 33Oosterlynck DJ, Meuleman C, Waer M, Vandeputte M, Koninckx PR. The natural killer activity of peritoneal fluid lymphocytes is decreased in women with endometriosis. Fertil Steril. 1992; 58(2): 290-295. - 34Funamizu A, Fukui A, Kamoi M, et al. Expression of natural cytotoxicity receptors on peritoneal fluid natural killer cell and cytokine production by peritoneal fluid natural killer cell in women with endometriosis. Am J Reprod Immunol. 2014; 71(4): 359-367. - 35Ho HN, Chao KH, Chen HF, Wu MY, Yang YS, Lee TY. Peritoneal natural killer cytotoxicity and CD25+ CD3+ lymphocyte subpopulation are decreased in women with stage III-IV endometriosis. Hum Reprod. 1995; 10(10): 2671-2675. - 36Khan KN, Yamamoto K, Fujishita A, et al. Association between FOXP3(+) regulatory T-cells and occurrence of peritoneal lesions in women with ovarian endometrioma and dermoid cysts. Reprod Biomed Online. 2019; 38(6): 857-869. - 37Khan KN, Yamamoto K, Fujishita A, et al. Differential levels of regulatory T cells and T-Helper-17 cells in women with early and advanced endometriosis. J Clin Endocrinol Metab. 2019; 104(10): 4715-4729. - 38Huang J, Chen X, Lv Y. HMGB1 Mediated inflammation and autophagy contribute to endometriosis. Front Endocrinol (Lausanne). 2021; 12:616696. - 39Yun BH, Chon SJ, Choi YS, Cho S, Lee BS, Seo SK. Pathophysiology of endometriosis: role of high mobility group box-1 and toll-like receptor 4 developing inflammation in endometrium. PLoS One. 2016; 11(2):e0148165. - 40Cao Y, Liu X, Guo SW. Plasma high mobility group box 1 (HMGB1), osteopontin (OPN), and hyaluronic acid (HA) as admissible biomarkers for endometriosis. Sci Rep. 2019; 9(1): 9272. - 41Miller JE, Lingegowda H, Symons LK, et al. IL-33 activates group 2 innate lymphoid cell expansion and modulates endometriosis. JCI Insight. 2021; 6(23):e149699. - 42Cao X, Yang D, Song M, Murphy A, Parthasarathy S. The presence of endometrial cells in the peritoneal cavity enhances monocyte recruitment and induces inflammatory cytokines in mice: implications for endometriosis. Fertil Steril. 2004; 82(3): 999-1007. Suppl. - 43Chun S, Kim H, Ku SY, Suh CS, Kim SH, Kim JG. The association between endometriosis and polymorphisms in the interleukin-1 family genes in Korean women. Am J Reprod Immunol. 2012; 68(2): 154-163. - 44Hudelist G, Lass H, Keckstein J, et al. Interleukin 1alpha and tissue-lytic matrix metalloproteinase-1 are elevated in ectopic endometrium of patients with endometriosis. Hum Reprod. 2005; 20(6): 1695-1701. - 45Ferrero S, Gillott DJ, Remorgida V, Anserini P, Ragni N, Grudzinskas JG. GnRH analogue remarkably down-regulates inflammatory proteins in peritoneal fluid proteome of women with endometriosis. J Reprod Med. 2009; 54(4): 223-231. - 46Hayrabedyan S, Kyurkchiev S, Kehayov I. FGF-1 and S100A13 possibly contribute to angiogenesis in endometriosis. J Reprod Immunol. 2005; 67(1-2): 87-101. - 47Jaeger-Lansky A, Schmidthaler K, Kuessel L, et al. Local and systemic levels of cytokines and danger signals in endometriosis-affected women. J Reprod Immunol. 2018; 130: 7-10. - 48Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012; 481(7381): 278-286. - 49Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell. 2014; 157(5): 1013-1022. - 50Broz P, Pelegrin P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020; 20(3): 143-157. - 51Akbar AN, Vukmanovic-Stejic M, Taams LS, Macallan DC. The dynamic co-evolution of memory and regulatory CD4+ T cells in the periphery. Nat Rev Immunol. 2007; 7(3): 231-237. - 52Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005; 6(4): 345-352. - 53Parekh VV, Wilson MT, Olivares-Villagomez D, et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J Clin Invest. 2005; 115(9): 2572-2583. - 54Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012; 122(3): 787-795. - 55Zhang YH, He M, Wang Y, Liao AH. Modulators of the balance between M1 and M2 macrophages during pregnancy. Front Immunol. 2017; 8: 120. - 56Fedotcheva TA, Fedotcheva NI, Shimanovsky NL. Progesterone as an anti-inflammatory drug and immunomodulator: new aspects in hormonal regulation of the inflammation. Biomolecules. 2022; 12(9). - 57Koubovec D, Ronacher K, Stubsrud E, Louw A, Hapgood JP. Synthetic progestins used in HRT have different glucocorticoid agonist properties. Mol Cell Endocrinol. 2005; 242(1–2): 23-32. - 58Enomoto LM, Kloberdanz KJ, Mack DG, Elizabeth D, Weinberg A. Ex vivo effect of estrogen and progesterone compared with dexamethasone on cell-mediated immunity of HIV-infected and uninfected subjects. J Acquir Immune Defic Syndr. 2007; 45(2): 137-143. - 59Piccinni MP, Giudizi MG, Biagiotti R, et al. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol. 1995; 155(1): 128-133. - 60Xiu F, Anipindi VC, Nguyen PV, et al. High physiological concentrations of progesterone reverse estradiol-mediated changes in differentiation and functions of bone marrow derived dendritic cells. PLoS One. 2016; 11(4):e0153304. 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Condition tags

endometriosisadenomyosischronic_pelvic_paindysmenorrheadyspareuniainfertility

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Alarmins Alarmins Alarmins Alarmins

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