Human Chorionic Gonadotropin modulates CXCL10 Expression through Histone Methylation in human decidua

Abstract

the process of implantation, trophoblast invasion and placentation demand continuous adaptation and modifications between the trophoblast (embryonic) and the decidua (maternal). Within the decidua, the maternal immune system undergoes continued changes, as the pregnancy progress, in terms of the cell population, phenotype and production of immune factors, cytokines and chemokines. Human chorionic gonadotropin (hCG) is one of the earliest hormones produced by the blastocyst and has potent immune modulatory effects, especially in relation to T cells. We hypothesized that trophoblastderived hcG modulates the immune population present at the maternal fetal interface by modifying the cytokine profile produced by the stromal/decidual cells. Using in vitro models from decidual samples we demonstrate that hcG inhibits CXCL10 expression by inducing H3K27me3 histone methylation, which binds to Region 4 of the CXCL10 promoter, thereby suppressing its expression. hCG-induced histone methylation is mediated through EZH2, a functional member of the PRC2 complex. Regulation of CXCL10 expression has a major impact on the capacity of endometrial stromal cells to recruit CD8 cells. We demonstrate the existence of a cross talk between the placenta (hCG) and the decidua (CXCL10) in the control of immune cell recruitment. Alterations in this immune regulatory function, such as during infection, will have detrimental effects on the success of the pregnancy. The coordinated balance between the invading trophoblast and a receptive maternal decidua is critical for the success of pregnancy 1,2. The process of implantation, trophoblast invasion and placentation demand continuous adaptation and modifications between the trophoblast (embryonic) and the decidua (maternal) 3-5. Within the decidua, the maternal immune system undergoes continued modifications, as the pregnancy progresses, in terms of the cell population, phenotype and production of immune factors, cytokines and chemokines 6. These adaptation processes are essential for the normal progression of the pregnancy. The decidua, the pregnant uterine endometrium, has long been considered as a supportive environment for the immune cells and the trophoblast present at the implantation site. However, growing evidence suggest that decidual stromal cells (DSCs) may play a more active role in the regulation of differentiation, migration and function of uterine immune cells 7 as well as in the protection against infections 8. Immune cells are a major cellular component of the human and rodents' pregnant uterus, and their specific role has been an area of active research. During the first trimester of the human pregnancy, 70% of the leukocytes found in the decidua are Natural Killer (NK) cells, 20% to 25% are macrophages, and approximately 1.7% are dendritic cells (DCs) 9-11. In addition, the uterine T cell population expands across gestation, and are mostly regulatory in nature 12. The recruitment of immune cells into the uterus is cell specific and their function is locally controlled 7 .

Peri‐implantation cytokine profile differs between singleton and twin IVF pregnancies

“…4,7,[21][22][23][24][25] CXCL10 secretion by endometrial cells is increased on day 14 of the menstrual cycle, and CXCL10 has been detected in endometrial aspirations prior to ET in IVF, 5,26 but secretion decreases by day 21 in humans who were not pregnant, 3 and also decreases in decidualized endometrium. 4 CXCL10 endometrial secretion, therefore, increases around the time of ovulation and fertilization, but decreases by the time of implantation, possibly to modulate its roles recruiting CD8+ T cells, promoting inflammation, and blocking angiogenesis. 4,20,[27][28][29] While CXCL10 may be important at the time of blastocyst-decidual apposition, it may be detrimental to the progression of implantation.…”

“…Details of the cohort have been described in previous publications. 4,9 Inclusion criteria for this prospective cohort study were female patients, ages 18-45, undergoing fresh or frozen blastocyst (day 5) ET with a serum β-hCG level >50 mIU/mL on the first serum draw, which was timed between days 9-12 following ET. Exclusion criteria were patients with chronic autoimmune disease (such as lupus, thyroid autoimmunity, ulcerative colitis, or Crohn's disease); diabetes and hypertension requiring medication; diagnosis of endometriosis confirmed by laparoscopy or endometriomas on imaging; or current illness (in general, we excluded patients with underlying inflammatory process).…”

“…[1][2][3] C-X-C motif chemokine ligand 10 (CXCL10) and tumor necrosis factor-alpha (TNF-α) are both pro-inflammatory cytokines known to be secreted by the human endometrium prior to implantation. 3,4 In patients undergoing in vitro fertilization (IVF), TNF-α and CXCL10 are both more highly concentrated in endometrial aspirations prior to embryo transfer (ET) in patients who achieve implantation compared to those who do not. 5,6 TNF-α is known to increase the transcription of other pro-inflammatory cytokines and recruitment of immune cells to the endometrium.…”

“…9 A progressive shift toward an anti-inflammatory or immune tolerant environment was observed as healthy pregnancies progress in the first trimester, reflected in declining serum TNF-α and increasing IL-10 levels with advancing gestation, 9 and decreasing CXCL10/ β-human chorionic gonadotropin (β-hCG) ratio in early gestation. 4 Produced by the invading syncytiotrophoblast, β-hCG is known to suppress the CXCL10 promoter through histone methylation, thus reducing CXCL10 expression in the decidua. 4 A failing pregnancy has a cytokine expression profile consistent with heightened inflammation lasting for too long.…”

“…4 Produced by the invading syncytiotrophoblast, β-hCG is known to suppress the CXCL10 promoter through histone methylation, thus reducing CXCL10 expression in the decidua. 4 A failing pregnancy has a cytokine expression profile consistent with heightened inflammation lasting for too long. 2,9,10 Our collective understanding on whether maternal immune responses and circulating cytokine profiles differ between singleton and multiple implantations is lacking.…”