https://doi.org/10.4081/ejh.2024.4052

CCL18 promotes endometriosis by increasing endometrial cell migration and neuroangiogenesis

Vol. 68 No. 3 (2024)
Submitted: 22 April 2024
Accepted: 10 July 2024
Published: 6 August 2024
CCL18, CCR8, endometriosis, macrophage, neuroangiogenesis
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Authors

Yangying Peng
pengyy20220329@163.com
https://orcid.org/0000-0003-3280-3820
Department of Obstetrics and Gynecology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou; Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, China.
Shaojie Ding
Department of Obstetrics and Gynecology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Ping Xu
Department of Obstetrics and Gynecology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Xueyan Zhang
Department of Obstetrics and Gynecology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Jianzhang Wang
Department of Obstetrics and Gynecology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Tiantian Li
Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Liyun Liao
Xiangshan First People’s Hospital Medical and Health Group, Ningbo, China.
Xinmei Zhang
https://orcid.org/0000-0001-7122-6435
Department of Obstetrics and Gynecology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Endometriosis is an estrogen-dependent inflammatory gynecological disease whose pathogenesis is unclear. C-C motif chemokine ligand 18 (CCL18), a chemokine, is involved in several inflammatory diseases. In this study, we aimed to investigate the role of CCL18 in endometriosis and its underlying mechanisms. Human endometrium and peritoneal fluid were obtained from women with and without endometriosis for molecular studies. The expression level of CCL18 in each tissue sample was examined by RNA sequencing analysis, quantitative PCR analysis and immunohistochemistry staining. The effects of CCL18 on cell migration, tube formation and neurite growth were investigated in vitro using primary endometrial cells, human umbilical vein endothelial cells (HUVECs) and dorsal root ganglion (DRG) neurons, respectively. Moreover, the development of endometriosis in mice was studied in vivo by blocking CCL18. CCL18 was shown to be overexpressed in endometrial foci and peritoneal fluid in women with endometriosis and was positively correlated with endometriosis pain. In vitro, CCL18 promoted the migration of ectopic endometrial cells, tube formation of HUVECs, and nerve outgrowth of DRG neurons. More importantly, inhibition of CCL18 significantly suppressed lesion development, angiogenesis, and nerve infiltration in a mouse model of endometriosis. In conclusion, CCL18 may play a role in the progression of endometriosis by increasing endometrial cell migration and promoting neuroangiogenesis.

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Scopus
Google Scholar
Europe PMC
Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet 2021;397:839-52. DOI: https://doi.org/10.1016/S0140-6736(21)00389-5
La Rosa VL, De Franciscis P, Barra F, Schiattarella A, Tropea A, Tesarik J, et al. Sexuality in women with endometriosis: a critical narrative review. Minerva Med 2020;111:79-89. DOI: https://doi.org/10.23736/S0026-4806.19.06299-2
Rizk B, Fischer AS, Lotfy HA, Turki R, Zahed HA, Malik R, et al. Recurrence of endometriosis after hysterectomy. Facts Views Vis Obgyn 2014;6:219-27.
Vallvé-Juanico J, Houshdaran S, Giudice LC. The endometrial immune environment of women with endometriosis. Hum Reprod Update 2019;25:564-91. DOI: https://doi.org/10.1093/humupd/dmz018
Laskin DL, Sunil VR, Gardner CR, Laskin JD. Macrophages and tissue injury: agents of defense or destruction? Annu Rev Pharmacol Toxicol 2011;51:267-88. DOI: https://doi.org/10.1146/annurev.pharmtox.010909.105812
Chen P, Bonaldo P. Role of macrophage polarization in tumor angiogenesis and vessel normalization. Int Rev Cell Mol Biol 2013;301:1-35. DOI: https://doi.org/10.1016/B978-0-12-407704-1.00001-4
Schmid S, Le U-T, Haager B, Mayer O, Dietrich I, Elze M, et al. Local concentrations of CC-Chemokine-Ligand 18 correlate with tumor size in non-small cell lung cancer and are elevated in lymph node-positive disease. Anticancer Res 2016;36:4667-71. DOI: https://doi.org/10.21873/anticanres.11018
Mertens JS, Jong EMGJd, Hoogen LLvd, Wienke J, Thurlings RM, Seyger MMB, et al. The identification of CCL18 as biomarker of disease activity in localized scleroderma. J Autoimmun 2019;101:86-93. DOI: https://doi.org/10.1016/j.jaut.2019.04.008
Pochetuhen K, Luzina IG, Lockatell V, Choi J, Todd NW, Atamas SP. Complex regulation of pulmonary inflammation and fibrosis by CCL18. Am J Pathol 2007;171:428-37. DOI: https://doi.org/10.2353/ajpath.2007.061167
Liu X, Xu X, Deng W, Huang M, Wu Y, Zhou Z, et al. CCL18 enhances migration, invasion and EMT by binding CCR8 in bladder cancer cells. Mol Med Rep 2019;19:1678-86. DOI: https://doi.org/10.3892/mmr.2018.9791
Lin L, Chen Y-S, Yao Y-D, Chen J-Q, Chen J-N, Huang S-Y, et al. CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. Oncotarget 2015;6:34758-73. DOI: https://doi.org/10.18632/oncotarget.5325
Yang Y-Z, Zhang W, Zhao B-B, Li L. Expression of CCL18 gene in ovarian cancer and its impact on the biologic function of ovarian cancer cells. Int J Clin Exp Pathol 2019;12:2572-84.
Li G, Lin Y, Zhang Y, Gu N, Yang B, Shan S, et al. Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis. Cell Death Discov 2022;8:29. DOI: https://doi.org/10.1038/s41420-022-00821-z
Greaves E, Collins F, Esnal-Zufiaurre A, Giakoumelou S, Horne AW, Saunders PTK. Estrogen receptor (ER) agonists differentially regulate neuroangiogenesis in peritoneal endometriosis via the repellent factor SLIT3. Endocrinology 2014;155:4015-26. DOI: https://doi.org/10.1210/en.2014-1086
Dodds KN, Beckett EAH, Evans SF, Hutchinson MR. Lesion development is modulated by the natural estrous cycle and mouse strain in a minimally invasive model of endometriosis. Biol Reprod 2017;97:810-21. DOI: https://doi.org/10.1093/biolre/iox132
Somigliana E, Viganò P, Rossi G, Carinelli S, Vignali M, Panina-Bordignon P. Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis. Hum Reprod 1999;14:2944-50. DOI: https://doi.org/10.1093/humrep/14.12.2944
Wang L, Jenkins TJ, Dai M, et al. Antagonism of chemokine receptor CCR8 is ineffective in a primate model of asthma. Thorax 2013;68:506-12. DOI: https://doi.org/10.1136/thoraxjnl-2012-203012
Ricci AG, Olivares CN, Bilotas MA, Bastón JI, Singla JJ, Meresman GF, et al. Natural therapies assessment for the treatment of endometriosis. Hum Reprod 2013;28:178-88. DOI: https://doi.org/10.1093/humrep/des369
Ricci AG, Olivares CN, Bilotas MA, Meresman GF, Barañao RI. Effect of vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis. Reprod Sci 2011;18:614-22. DOI: https://doi.org/10.1177/1933719110395406
Gardella B, Dominoni M, Gritti A, Arrigo A, Antonucci S, Carletti GV, et al. Endometriosis pain and epithelial neutrophil activating peptide-78 levels. Sci Rep 2022;12:3227. DOI: https://doi.org/10.1038/s41598-022-07349-3
Jing X, Peng J, Dou Y, Sun J, Ma C, Wang Q, et al. Macrophage ERα promoted invasion of endometrial cancer cell by mTOR/KIF5B-mediated epithelial to mesenchymal transition. Immunol Cell Biol 2019;97:563-76. DOI: https://doi.org/10.1111/imcb.12245
Liu J, Wang Y, Chen P, Ma Y, Wang S, Tian Y, et al. AC002454.1 and CDK6 synergistically promote endometrial cell migration and invasion in endometriosis. Reproduction 2019;157:535-43. DOI: https://doi.org/10.1530/REP-19-0005
Li J, Ma J, Fei X, Zhang T, Zhou J, Lin J. Roles of cell migration and invasion mediated by Twist in endometriosis. J Obstet Gynaecol Res 2019;45:1488-96. DOI: https://doi.org/10.1111/jog.14001
Rocha ALL, Reis FM, Taylor RN. Angiogenesis and endometriosis. Obstet Gynecol Int 2013:859619. DOI: https://doi.org/10.1155/2013/859619
McKinnon B, Bersinger NA, Wotzkow C, Mueller MD. Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations. Fertil Steril 2012;97:373-80. DOI: https://doi.org/10.1016/j.fertnstert.2011.11.011

Ethics Approval

the experimental protocols were approved by the Ethics Committee of the Women’s Hospital, Zhejiang University School of Medicine., The treatment of the mice in this study was approved by the Ethics Committee of Animal Laboratory, Zhejiang University

Supporting Agencies

Natural Science Foundation of Zhejiang Province, National Natural Science Foundation of China

How to Cite

Peng, Y., Ding, S., Xu, P., Zhang, X., Wang, J., Li, T., Liao, L., & Zhang, X. (2024). CCL18 promotes endometriosis by increasing endometrial cell migration and neuroangiogenesis. European Journal of Histochemistry, 68(3). https://doi.org/10.4081/ejh.2024.4052
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