Estradiol and Progesterone Regulate the Migration of Mast Cells from the Periphery to the Uterus and Induce Their Maturation and Degranulation

Abstract

BackgroundMast cells (MCs) have long been suspected as important players for implantation based on the fact that their degranulation causes the release of pivotal factors, e.g., histamine, MMPs, tryptase and VEGF, which are known to be involved in the attachment and posterior invasion of the embryo into the uterus. Moreover, MC degranulation correlates with angiogenesis during pregnancy. The number of MCs in the uterus has been shown to fluctuate during menstrual cycle in human and estrus cycle in rat and mouse indicating a hormonal influence on their recruitment from the periphery to the uterus. However, the mechanisms behind MC migration to the uterus are still unknown.Methodology/Principal FindingsWe first utilized migration assays to show that MCs are able to migrate to the uterus and to the fetal-maternal interface upon up-regulation of the expression of chemokine receptors by hormonal changes. By using a model of ovariectomized animals, we provide clear evidences that also in vivo, estradiol and progesterone attract MC to the uterus and further provoke their maturation and degranulation.Conclusion/SignificanceWe propose that estradiol and progesterone modulate the migration of MCs from the periphery to the uterus and their degranulation, which may prepare the uterus for implantation.

Adaptive Immune Responses During Pregnancy

“…55,56 Estrogen and progesterone in combination were necessary for the recruitment of mast cells (MCs) to the uterus. 57 MCs were recently reported to be pivotal for implantation and placentation. 58 The most important pregnancy hormone, the human chorionic gonadotropin (hCG) secreted by the trophoblasts, was shown to attract regulatory T cells to the fetalmaternal interface 59 but also to foster their suppressive function.…”

Immunoprofiling of human uterine mast cells identifies three phenotypes and expression of ERβ and glucocorticoid receptor

“…Although, other authors have previously demonstrated a direct effect of female sex hormones on MC behaviour, activation and migration, in those studies they cited activation of MCs via ERα and PR ( Jensen et al ., 2010; Zaitsu et al ., 2007). In this study, based on detailed immunohistochemical analysis, using previously validated antibodies directed against oestrogen receptor subtypes ( Critchley et al ., 2002; Henderson et al ., 2003), we found novel evidence for immunoexpression of ERβ, but no evidence of expression of ERα.…”

“…The female sex hormones, oestradiol and progesterone, are thought to have an impact on MCs because many pathophysiological conditions attributed to MC activity have a higher prevalence in females than males ( Narita et al ., 2007). Studies in non-reproductive tissue systems and those using the HMC-1 cell line (human MC line, ( Butterfield et al ., 1988)) have reported that MCs express the oestrogen receptor α isoform (ERα) and progesterone receptor (PR) ( Jensen et al ., 2010; Nicovani & Rudolph, 2002; Zaitsu et al ., 2007). Some authors found evidence that MCs can be rapidly stimulated to degranulate by oestradiol via ERα ( Zaitsu et al ., 2007).…”

In vivo visualization of uterine mast cells by two-photon microscopy

“…Their effects are mainly mediated by granule-stored mediators such as metalloproteases, MC-specific proteases, tissue plasminogen activator (tPA), vascular endothelial growth factor (VEGF), transforming growth factor b (TGFb) (Galli et al 2005) and galectin 1 (Gal1, Woidacki et al 2013) that are released upon activation. We have recently reported that MCs migrate from the periphery to the uterus responding to hormonal fluctuations (Jensen et al 2010). This has already suggested their importance for pregnancy, a period characterized by great hormonal changes.…”

“…1B) to reduce uterine contractions. As MCs are mainly located in the uterus rather than in placental tissue (Woidacki K, Zenclussen AC, 2010; unpublished observations), we avoided damage to the uterine wall, a procedure shown to be beneficial for imaging of the placenta (Zenclussen et al 2012). Therefore, the focus was on the mesometrial side of the intact uterus (Fig.…”