Excess Heme Promotes the Migration and Infiltration of Macrophages in Endometrial Hyperplasia Complicated with Abnormal Uterine Bleeding
Lu-Yu Ruan,
Zhen-Zhen Lai,
Jia-Wei Shi,
Hui-Li Yang,
Jiang-Feng Ye,
Feng Xie,
Xue-Min Qiu,
Xiao-Yong Zhu,
Ming-Qing Li
Affiliations
Lu-Yu Ruan
NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
Zhen-Zhen Lai
Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
Jia-Wei Shi
Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
Hui-Li Yang
Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
Jiang-Feng Ye
Institute for Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138632, Singapore
Feng Xie
Medical Center of Diagnosis and Treatment for Cervical and Intrauterine Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
Xue-Min Qiu
Clinical Research Center, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
Xiao-Yong Zhu
Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
Ming-Qing Li
NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
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.
