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However, the role of excess heme in the migration and infiltration of immune cells in EH complicated by AUB remains unknown. In this study, 45 patients with AUB were divided into three groups: a proliferative phase group (n = 15), a secretory phase group (n = 15) and EH (n = 15). We observed that immune cell subpopulations were significantly different among the three groups, as demonstrated by flow cytometry analysis. Of note, there was a higher infiltration of total immune cells and macrophages in the endometrium of patients with EH. Heme up-regulated the expression of heme oxygenase-1 (HO-1) and nuclear factor erythroid-2-related factor 2 (Nrf2) in endometrial epithelial cells (EECs) in vitro, as well as chemokine (e.g., CCL2, CCL3, CCL5, CXCL8) levels. Additionally, stimulation with heme led to the increased recruitment of THP-1 cells in an indirect EEC-THP-1 co-culture unit. These data suggest that sustained and excessive heme in patients with AUB may recruit macrophages by increasing the levels of several chemokines, contributing to the accumulation and infiltration of macrophages in the endometrium of EH patients, and the key molecules of heme metabolism, HO-1 and Nrf2, are also involved in this regulatory process.<\/jats:p>","DOI":"10.3390\/biom12060849","type":"journal-article","created":{"date-parts":[[2022,6,19]],"date-time":"2022-06-19T10:14:52Z","timestamp":1655633692000},"page":"849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Excess Heme Promotes the Migration and Infiltration of Macrophages in Endometrial Hyperplasia Complicated with Abnormal Uterine Bleeding"],"prefix":"10.3390","volume":"12","author":[{"given":"Lu-Yu","family":"Ruan","sequence":"first","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"},{"name":"Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Zhen","family":"Lai","sequence":"additional","affiliation":[{"name":"Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Wei","family":"Shi","sequence":"additional","affiliation":[{"name":"Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Li","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang-Feng","family":"Ye","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138632, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xie","sequence":"additional","affiliation":[{"name":"Medical Center of Diagnosis and Treatment for Cervical and Intrauterine Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Min","family":"Qiu","sequence":"additional","affiliation":[{"name":"Clinical Research Center, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2512-9703","authenticated-orcid":false,"given":"Xiao-Yong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9276-0722","authenticated-orcid":false,"given":"Ming-Qing","family":"Li","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"},{"name":"Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1073\/pnas.92.5.1391","article-title":"A macrophage receptor for oxidized low density lipoprotein distinct from the receptor for acetyl low density lipoprotein: Partial purification and role in recognition of oxidatively damaged cells","volume":"92","author":"Ottnad","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1159\/000321390","article-title":"Comparison of the efficacy of three progestins in the treatment of simple endometrial hyperplasia without atypia","volume":"72","author":"Ozdegirmenci","year":"2011","journal-title":"Gynecol. Obstet. Invest."},{"key":"ref_3","first-page":"232","article-title":"New concepts for an old problem: The diagnosis of endometrial hyperplasia","volume":"23","author":"Sanderson","year":"2017","journal-title":"Hum. Reprod. Update"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e13295","DOI":"10.1111\/aji.13295","article-title":"Changes in subsets of immunocytes in endometrial hyperplasia","volume":"84","author":"Lai","year":"2020","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.7314\/APJCP.2014.15.4.1689","article-title":"Are neutrophil\/lymphocyte and platelet\/lymphocyte ratios associated with endometrial precancerous and cancerous lesions in patients with abnormal uterine bleeding?","volume":"15","author":"Acmaz","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1055\/s-0037-1603807","article-title":"Abnormal Uterine Bleeding","volume":"39","author":"Rosa","year":"2017","journal-title":"Rev. Bras. Ginecol. Obstet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.12703\/P7-33","article-title":"Recent advances in managing and understanding menstrual disorders","volume":"7","author":"Bahamondes","year":"2015","journal-title":"F1000Prime Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1093\/bmb\/ldx027","article-title":"Abnormal uterine bleeding","volume":"123","author":"Cheong","year":"2017","journal-title":"Br. Med. Bull."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/ijgo.12666","article-title":"The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions","volume":"143","author":"Munro","year":"2018","journal-title":"Int J. Gynaecol. Obstet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.mayocp.2018.12.012","article-title":"Evaluation and Management of Abnormal Uterine Bleeding","volume":"94","author":"Marnach","year":"2019","journal-title":"Mayo Clin. Proc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/1471-0528.14431","article-title":"Research and clinical management for women with abnormal uterine bleeding in the reproductive years: More than PALM-COEIN","volume":"124","author":"Munro","year":"2017","journal-title":"BJOG"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.coi.2017.10.005","article-title":"Heme and hemolysis in innate immunity: Adding insult to injury","volume":"50","author":"Martins","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1530\/REP-19-0028","article-title":"Elevated heme impairs macrophage phagocytosis in endometriosis","volume":"158","author":"Liu","year":"2019","journal-title":"Reproduction"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.canlet.2018.10.019","article-title":"A20-mediated deubiquitination of ERalpha in the microenvironment of CD163(+) macrophages sensitizes endometrial cancer cells to estrogen","volume":"442","author":"Lv","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.7150\/ijbs.61073","article-title":"Heme oxygenase 1: A novel oncogene in multiple gynecological cancers","volume":"17","author":"Lu","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pradhan, P., Vijayan, V., Gueler, F., and Immenschuh, S. (2020). Interplay of Heme with Macrophages in Homeostasis and Inflammation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030740"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1093\/humupd\/dmaa038","article-title":"Immunological changes associated with adenomyosis: A systematic review","volume":"27","author":"Bourdon","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00404-020-05840-8","article-title":"Prevalence of adenomyosis in endometrial cancer patients: A systematic review and meta-analysis","volume":"303","author":"Raffone","year":"2021","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1093\/humrep\/del205","article-title":"Differential infiltration of macrophages and prostaglandin production by different uterine leiomyomas","volume":"21","author":"Miura","year":"2006","journal-title":"Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1677\/JOE-10-0072","article-title":"Inflammatory events in endometrial adenocarcinoma","volume":"206","author":"Wallace","year":"2010","journal-title":"J. Endocrinol."},{"key":"ref_21","first-page":"387","article-title":"Immunology of normal and abnormal menstruation","volume":"9","author":"Berbic","year":"2013","journal-title":"Womens Health"},{"key":"ref_22","first-page":"296","article-title":"Endometrial immunocompetent cells in proliferative and secretory phase of normal menstrual cycle","volume":"79","author":"Trandafilovic","year":"2019","journal-title":"Folia Morphol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/humupd\/6.1.16","article-title":"Endometrial leukocytes and menstruation","volume":"6","author":"Salamonsen","year":"2000","journal-title":"Hum. Reprod. Update"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0165-0378(99)00002-9","article-title":"Menstruation: Induction by matrix metalloproteinases and inflammatory cells","volume":"44","author":"Salamonsen","year":"1999","journal-title":"J. Reprod. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"316","DOI":"10.5114\/ceji.2019.89610","article-title":"Comparison of T and NK lymphocyte subsets between human endometrial tissue and peripheral blood","volume":"44","author":"Chernyshov","year":"2019","journal-title":"Cent. Eur. J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/ni.1841","article-title":"Raising the NKT cell family","volume":"11","author":"Godfrey","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/0167-5699(91)90014-K","article-title":"On the nature and function of human uterine granular lymphocytes","volume":"12","author":"King","year":"1991","journal-title":"Immunol. Today"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/0198-8859(96)00120-6","article-title":"Activation status of T and NK cells in the endometrium throughout menstrual cycle and normal and abnormal early pregnancy","volume":"49","author":"Ho","year":"1996","journal-title":"Hum. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5528","DOI":"10.1210\/jc.2005-0688","article-title":"Menopausal hormone therapy and irregular endometrial bleeding: A potential role for uterine natural killer cells?","volume":"90","author":"Hickey","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.humpath.2009.06.012","article-title":"Increased natural killer cells and decreased regulatory T cells are seen in complex atypical endometrial hyperplasia and well-differentiated carcinoma treated with progestins","volume":"41","author":"Witkiewicz","year":"2010","journal-title":"Hum. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s00441-006-0358-2","article-title":"Neutrophil depletion retards endometrial repair in a mouse model","volume":"328","author":"Morison","year":"2007","journal-title":"Cell Tissue Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16","DOI":"10.4110\/in.2015.15.1.16","article-title":"Immune cells in the female reproductive tract","volume":"15","author":"Lee","year":"2015","journal-title":"Immune Netw."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nri3819","article-title":"The role of sex hormones in immune protection of the female reproductive tract","volume":"15","author":"Wira","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0020-7292(92)90974-N","article-title":"Macrophage- and lymphocyte-subtypes in the endometrium during different phases of the ovarian cycle","volume":"37","author":"Bonatz","year":"1992","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1093\/humrep\/den393","article-title":"Macrophage expression in endometrium of women with and without endometriosis","volume":"24","author":"Berbic","year":"2009","journal-title":"Hum. Reprod."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1111\/rda.12567","article-title":"Resident Macrophages and Lymphocytes in the Canine Endometrium","volume":"50","author":"Pires","year":"2015","journal-title":"Reprod. Domest. Anim."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.immuni.2010.08.012","article-title":"Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors","volume":"33","author":"Cros","year":"2010","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s00005-019-00552-7","article-title":"Role of Macrophages in Pregnancy and Related Complications","volume":"67","author":"Jena","year":"2019","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/cam4.445","article-title":"An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations","volume":"4","author":"Yang","year":"2015","journal-title":"Cancer Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1111\/j.1349-7006.2001.tb01154.x","article-title":"Preventive effects of isoflavones, genistein and daidzein, on estradiol-17beta-related endometrial carcinogenesis in mice","volume":"92","author":"Lian","year":"2001","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1182\/blood-2006-11-055723","article-title":"Targeting of heat shock protein 32 (Hsp32)\/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: A novel approach to overcome resistance against imatinib","volume":"111","author":"Mayerhofer","year":"2008","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1159\/000354524","article-title":"Clofibrate induces heme oxygenase 1 expression through a PPARalpha-independent mechanism in human cancer cells","volume":"32","author":"Wang","year":"2013","journal-title":"Cell Physiol. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1124\/pr.55.3.5","article-title":"Different faces of the heme-heme oxygenase system in inflammation","volume":"55","author":"Wagener","year":"2003","journal-title":"Pharmacol. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1139\/cjpp-2019-0287","article-title":"Amelioration of estrogen-induced endometrial hyperplasia in female rats by hemin via heme-oxygenase-1 expression, suppression of iNOS, p38 MAPK, and Ki67","volume":"97","author":"Ali","year":"2019","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.bcp.2018.02.010","article-title":"The macrophage heme-heme oxygenase-1 system and its role in inflammation","volume":"153","author":"Vijayan","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1097\/MOH.0000000000000423","article-title":"Hemolysis and immune regulation","volume":"25","author":"Zhong","year":"2018","journal-title":"Curr. Opin. Hematol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1136\/annrheumdis-2016-210426","article-title":"CCL2\/CCR2, but not CCL5\/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis","volume":"76","author":"Raghu","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1161\/01.RES.0000247067.34173.1b","article-title":"Constitutive endocytosis of CD163 mediates hemoglobin-heme uptake and determines the noninflammatory and protective transcriptional response of macrophages to hemoglobin","volume":"99","author":"Schaer","year":"2006","journal-title":"Circ. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.2174\/1381612824666180716163845","article-title":"M1\/M2 Macrophages in Diabetic Nephropathy: Nrf2\/HO-1 as Therapeutic Targets","volume":"24","author":"Landis","year":"2018","journal-title":"Curr. Pharm. Des."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/6\/849\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:35:10Z","timestamp":1760139310000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/6\/849"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,19]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["biom12060849"],"URL":"https:\/\/doi.org\/10.3390\/biom12060849","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,19]]}}}