The Regulatory Roles of Chemerin-Chemokine-Like Receptor 1 Axis in Placental Development and Vascular Remodeling During Early Pregnancy

Abstract

Chemerin is an adipokine that regulates metabolism in pregnancy. An elevation of serum chemerin level is associated with pregnancy complications. Consistently, we demonstrated that the chemerin expression was increased in placenta of preeclamptic patients at deliveries. The G protein-coupled receptor chemokine-like receptor 1 (CMKLR1) mediates the actions of chemerin. The functions of the chemerin-CMKLR1 axis in maintaining pregnancy are still unknown. In this study, we demonstrated that CMKLR1 was expressed in the decidual natural killer (dNK) cells and chorionic villi of human. Chemerin suppressed the proliferation of the dNK cells in vitro. Specific antagonist of CMKLR1, α-Neta abolished the suppressive effect of spent medium from chemerin-treated dNK cells culture on extravillous trophoblast invasion. Activation of the chemerin-CMKLR1 axis promoted fusion and differentiation of human cytotrophoblast to syncytiotrophoblast in vitro. We generated Cmklr1 knockout mice and showed that the Cmklr1 deficiency negatively affected pregnancy outcome in terms of number of implantation sites, litter size and fetal weight at birth. Histologically, the Cmklr1 deficiency impaired formation of the syncytiotrophoblast layer II, induced enlargement of the maternal lacunae in the labyrinth, increased the diameter of the spiral arteries and increased trophoblast invasion in the decidua. The Cmklr1 deficient placenta also displayed an increased number of dNK cells and serum IL-15 level. In summary, the chemerin-CMKLR1 axis regulated placental development and spiral artery remodeling in early pregnancy.

Understanding the Role of Chemerin in the Pathophysiology of Pre-Eclampsia

“…The Cmklr1-knockout mice presented histological changes indicating an increased diameter of spiral arteries and increased trophoblast invasion in the decidua but also an increased number of NK cells in the placental tissue, as well as an elevated serum IL-15 level, which is known for playing an important role in the development, survival, and activation of NK cells. On the basis of these findings, the authors concluded that chemerin and CMKLR1 are involved in the regulation of the secretion of trophoblast regulatory factors from decidual NK cells, including TNF-α, IL-10, and IL8, affecting in this way placental development and spiral artery remodeling [ 84 ]. The other study group demonstrated high levels of CMKLR1 expression by the CD56 low peripheral blood NK (pbNK) cells and observed that chemerin significantly supports pbNK cell migration through DEC and ST cells, as well as dNK cell migration through ST cells via rapid ERK activation.…”

Chemerin: A Functional Adipokine in Reproductive Health and Diseases

“…The role of the chemerin/CMKLR signaling pathway in placentation has begun to emerge. Recently, r-chemerin was reported to promote the syncytialization of CTBs by using the in vitro model of human choriocarcinoma BeWo cells [ 82 ]. The r-chemerin also inhibited the proliferation of dNK cells in vitro, and the conditioned medium derived from the dNK cells pre-treated with r-chemerin significantly impaired the invasion of EVTs in vitro [ 82 ].…”

“…Recently, r-chemerin was reported to promote the syncytialization of CTBs by using the in vitro model of human choriocarcinoma BeWo cells [ 82 ]. The r-chemerin also inhibited the proliferation of dNK cells in vitro, and the conditioned medium derived from the dNK cells pre-treated with r-chemerin significantly impaired the invasion of EVTs in vitro [ 82 ]. Meanwhile, chemerin secretion was found to be enhanced in decidualized human endometrial stromal cells, and chemerin positively regulated the chemotaxis of NK cells and angiogenesis of HUVEC cells in vitro [ 81 ].…”

“…Cmklr1 −/− mice exhibited an enlarged diameter of the spiral arteries, enhanced trophoblast invasion, and an increased number of dNK cells in the decidual zone. The dysfunctional placentation due to Cmklr1 knockout ultimately affected the fetus’s growth and development [ 82 ]. These findings are also supported by an article, which reported that injection of 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA, an antagonist for CMKLR1) in mouse uterine horn during the early pregnancy resulted in the abortion of embryos [ 83 ].…”

Statins Prevent the Deleterious Consequences of Placental Chemerin Upregulation in Preeclampsia

“…[10][11][12] Chemerin is involved in angiogenesis and spiral artery remodeling and might trigger delivery. 13,14 However, it may also play a role in the development of preeclampsia, given that its concentrations in blood correlate positively with the severity of preeclampsia and adverse fetal outcomes. 14,15 In agreement with this concept, placental overexpression of chemerin in pregnant mice induced a preeclampsia-like syndrome, involving high blood pressure, proteinuria, endothelial dysfunction, fetal growth restriction, and an increased sFlt-1/ PlGF ratio.…”