Excess Heme Promotes the Migration and Infiltration of Macrophages in Endometrial Hyperplasia Complicated with Abnormal Uterine Bleeding

In patients, endometrial hyperplasia (EH) is often accompanied by abnormal uterine bleeding (AUB), which is prone to release large amounts of heme. 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.

[1]  Ming-qing Li,et al.  Heme oxygenase 1: a novel oncogene in multiple gynecological cancers , 2021, International journal of biological sciences.

[2]  F. Petraglia,et al.  Immunological changes associated with adenomyosis: a systematic review. , 2020, Human reproduction update.

[3]  L. Insabato,et al.  Prevalence of adenomyosis in endometrial cancer patients: a systematic review and meta-analysis , 2020, Archives of Gynecology and Obstetrics.

[4]  Hui-Hui Shen,et al.  Changes in subsets of immunocytes in endometrial hyperplasia , 2020, American journal of reproductive immunology.

[5]  F. Gueler,et al.  Interplay of Heme with Macrophages in Homeostasis and Inflammation , 2020, International journal of molecular sciences.

[6]  H. Čolović,et al.  Endometrial immunocompetent cells in proliferative and secretory phase of normal menstrual cycle. , 2020, Folia morphologica.

[7]  B. Dons’koi,et al.  Comparison of T and NK lymphocyte subsets between human endometrial tissue and peripheral blood , 2019, Central-European journal of immunology.

[8]  F. Ali,et al.  Amelioration of estrogen-induced endometrial hyperplasia in female rats by hemin via heme-oxygenase-1 expression, suppression of iNOS, p38MAPK and Ki67. , 2019, Canadian journal of physiology and pharmacology.

[9]  Kang Chen,et al.  Role of Macrophages in Pregnancy and Related Complications , 2019, Archivum Immunologiae et Therapiae Experimentalis.

[10]  Ming-qing Li,et al.  Elevated heme impairs macrophage phagocytosis in endometriosis. , 2019, Reproduction.

[11]  Congjian Xu,et al.  A20-mediated deubiquitination of ERα in the microenvironment of CD163+ macrophages sensitizes endometrial cancer cells to estrogen. , 2019, Cancer letters.

[12]  M. Munro,et al.  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 , 2018, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[13]  V. Vijayan,et al.  The macrophage heme-heme oxygenase-1 system and its role in inflammation. , 2018, Biochemical pharmacology.

[14]  K. Quimby,et al.  M1/M2 Macrophages in Diabetic Nephropathy: Nrf2/HO-1 as Therapeutic Targets. , 2018, Current pharmaceutical design.

[15]  K. Yazdanbakhsh,et al.  Hemolysis and immune regulation , 2018, Current opinion in hematology.

[16]  S. Knapp,et al.  Heme and hemolysis in innate immunity: adding insult to injury. , 2018, Current opinion in immunology.

[17]  M. Munro,et al.  Research and clinical management for women with abnormal uterine bleeding in the reproductive years: More than PALM‐COEIN , 2017, BJOG : an international journal of obstetrics and gynaecology.

[18]  W. Robinson,et al.  CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis , 2016, Annals of the rheumatic diseases.

[19]  M. Arends,et al.  New concepts for an old problem: the diagnosis of endometrial hyperplasia , 2016, Human reproduction update.

[20]  I. Cameron,et al.  Abnormal uterine bleeding , 2017, British medical bulletin.

[21]  R. Payan-Carreira,et al.  Resident Macrophages and Lymphocytes in the Canine Endometrium. , 2015, Reproduction in domestic animals = Zuchthygiene.

[22]  Flt.Lt. Paweena Phaliwong Evaluation and Management of Abnormal Uterine Bleeding , 2015 .

[23]  C. Peterson,et al.  An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations , 2015, Cancer medicine.

[24]  C. Wira,et al.  The role of sex hormones in immune protection of the female reproductive tract , 2015, Nature Reviews Immunology.

[25]  L. Bahamondes,et al.  Recent advances in managing and understanding menstrual disorders , 2015, F1000prime reports.

[26]  S. K. Lee,et al.  Immune Cells in the Female Reproductive Tract , 2015, Immune network.

[27]  H. Aksoy,et al.  Are neutrophil/lymphocyte and platelet/lymphocyte ratios associated with endometrial precancerous and cancerous lesions in patients with abnormal uterine bleeding? , 2014, Asian Pacific journal of cancer prevention : APJCP.

[28]  W. Ding,et al.  Clofibrate Induces Heme Oxygenase 1 Expression through a PPARα-Independent Mechanism in Human Cancer Cells , 2013, Cellular Physiology and Biochemistry.

[29]  I. Fraser,et al.  Immunology of Normal and Abnormal Menstruation , 2013, Women's health.

[30]  O. Ozdegirmenci,et al.  Comparison of the Efficacy of Three Progestins in the Treatment of Simple Endometrial Hyperplasia without Atypia , 2011, Gynecologic and Obstetric Investigation.

[31]  J. Casanova,et al.  Human CD14dim Monocytes Patrol and Sense Nucleic Acids and Viruses via TLR7 and TLR8 Receptors , 2010, Immunity.

[32]  D. Gibson,et al.  Inflammatory events in endometrial adenocarcinoma. , 2010, The Journal of endocrinology.

[33]  D. Godfrey,et al.  Raising the NKT cell family , 2010, Nature Immunology.

[34]  R. Kurman,et al.  Increased natural killer cells and decreased regulatory T cells are seen in complex atypical endometrial hyperplasia and well-differentiated carcinoma treated with progestins. , 2010, Human pathology.

[35]  I. Fraser,et al.  Macrophage expression in endometrium of women with and without endometriosis. , 2009, Human reproduction.

[36]  H. Maeda,et al.  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. , 2008, Blood.

[37]  L. Salamonsen,et al.  Neutrophil depletion retards endometrial repair in a mouse model , 2007, Cell and Tissue Research.

[38]  M. Kurrer,et al.  Constitutive Endocytosis of CD163 Mediates Hemoglobin-Heme Uptake and Determines the Noninflammatory and Protective Transcriptional Response of Macrophages to Hemoglobin , 2006, Circulation research.

[39]  H. Masuzaki,et al.  Differential infiltration of macrophages and prostaglandin production by different uterine leiomyomas. , 2006, Human reproduction.

[40]  C. Witt,et al.  Menopausal hormone therapy and irregular endometrial bleeding: a potential role for uterine natural killer cells? , 2005, The Journal of clinical endocrinology and metabolism.

[41]  Carl G. Figdor,et al.  Different Faces of the Heme-Heme Oxygenase System in Inflammation , 2003, Pharmacological Reviews.

[42]  Midori Hashimoto,et al.  Preventive Effects of Isoflavones, Genistein and Daidzein, on Estradiol‐17β‐related Endometrial Carcinogenesis in Mice , 2001, Japanese journal of cancer research : Gann.

[43]  L. Salamonsen,et al.  Endometrial leukocytes and menstruation. , 2000, Human reproduction update.

[44]  D. Woolley,et al.  Menstruation: induction by matrix metalloproteinases and inflammatory cells. , 1999, Journal of reproductive immunology.

[45]  Y. S. Yang,et al.  Activation status of T and NK cells in the endometrium throughout menstrual cycle and normal and abnormal early pregnancy. , 1996, Human immunology.

[46]  D. Steinberg,et al.  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. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[47]  L. Mettler,et al.  Macrophage‐ and lymphocyte‐subtypes in the endometrium during different phases of the ovarian cycle , 1992, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[48]  Y. W. Loke,et al.  On the nature and function of human uterine granular lymphocytes. , 1991, Immunology today.