The integrative roles of chemokines at the maternal–fetal interface in early pregnancy

Cellular & Molecular Immunology (2014) 11, 438–448 ß 2014 CSI and USTC. All rights reserved 1672-7681/14 $32.00 www.nature.com/cmi REVIEW The integrative roles of chemokines at the maternal–fetal interface in early pregnancy Mei-Rong Du1, Song-Cun Wang1 and Da-Jin Li Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal–maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. There are unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall. Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. It is increasingly evident that the gestational uterine microenvironment is characterized, at least in part, by the differential expression and secretion of chemokines that induce selective trafficking of leukocyte subsets to the maternal–fetal interface and regulate multiple events that are closely associated with normal pregnancy. Here, we review the expression and function of chemokines and their receptors at the maternal–fetal interface, with a special focus on chemokine as a key component in trophoblast invasiveness and placental angiogenesis, recruitment and instruction of immune cells so as to form a fetus-supporting milieu during pregnancy. The chemokine network is also involved in pregnancy complications. Cellular & Molecular Immunology (2014) 11, 438–448; doi:10.1038/cmi.2014.68; published online 11 August 2014 Keywords: chemokine; decidua; pregnancy; pregnant complications; trophoblast INTRODUCTION The intimate association between maternal and placental tissues elicits an interesting immunological paradox. Placental tissue contains paternal antigens, but under normal circumstances, the allogeneic fetus and placenta are not attacked by the maternal immune system. Interestingly, this tolerance to fetal antigens occurs in the presence of a large number of maternal leukocytes, almost all of which are members of the innate immune system. There is a delicate crosstalk and collaboration between fetus-derived trophoblast cells and maternally-derived cells during normal pregnancy to establish a unique maternal– fetal immune milieu that contributes to embryo survival and development in the uterus until parturition. Dysfunction in the interactions of trophoblasts and maternally-derived cells and dysregulation of maternal–fetal immune tolerance are highly linked to some pregnancy failures, such as miscarriage, preeclampsia, fetal growth restriction and so on. The chemokine/chemokine receptor interactions play roles in almost all facets of maternal–fetal crosstalk. In this review, we highlight the contribution of chemokines and their receptors at the maternal–fetal interface to the maintenance of normal pregnancy, especially to maternal–fetal tolerance and to placentation. Since normal pregnancy is a model of natural immune tolerance, pregnancy research may assist in the broader understanding of tumor immunology and of transplantation immunology. THE CHEMOKINE FAMILY The chemokines constitute a superfamily of small chemotactic cytokines. More than 50 chemokines and at least 20 chemokine Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University, Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China 1 M-RD and S-CW contributed equally to this work. Correspondence: Dr MR Du, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University, Shanghai Medical College, Shanghai 200011, China. E-mail: Or Dr DJ Li, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University, Shanghai Medical College, Shanghai 200011, China. E-mail: Received: 22 April 2014; Revised: 29 June 2014; Accepted: 1 July 2014 Roles of chemokine in early pregnancy MR Du et al 439 receptors have been identified.1,2 Chemokines exert their effects through G protein-coupled receptors.2 Based on their structural motif, including the number and position of two conserved cysteine residues, chemokines are classified into subfamilies: the CXC, CC, CX3C and C groups or the a, b, c and d subfamilies. Chemokine receptors are also divided into four corresponding groups.3 One or three amino acids separate the first and second cysteines in the CXC and CX3C chemokines, respectively, the two cysteines are adjoining in the CC subfamily, and the C subfamily lacks the first and pairing third conserved cystein residues. The fifth receptor subfamily, CX, reported only in zebrafish lacks the two N-terminal residues, but retains the third and fourth residues.4 The CXC family can be further subdivided by the presence or absence of a conserved ‘Glu-Leu-Arg’ (ELR) subsequence at the NH2 terminus. The ELR1 family is involved in angiogenesis and the ELR2 family is involved in angiostatic activity.5 The primary functions of chemokines are the directional stimulation of immune-cell adhesion and migration into the infected or inflamed tissue to initiate effective immune responses. However, chemokine functions are not restricted to chemotaxis but serve many other immune purposes such as dendritic cell (DC) maturation,6 B-cell antibody class switching,7 and T-cell activation and differentiation.8 Chemokines are also potent mediators of neoangiogenesis and tumor growth, invasion, and metastasis,9,10 and play a pivotal role in embryogenesis and organ transplantation.11 More recently, chemokine receptors with structural features that are inconsistent with a signalling function have been described. When ligated, these ‘silent’ (non-signalling) chemokine receptors do not elicit migration or conventional signalling responses, but regulate inflammatory and immune reactions in different ways, such as acting as decoys or scavengers. The availability of chemokines is regulated by three non-signalling decoy receptors: chemokine decoy receptor (D6), Duffy antigen receptor for chemokines (DARC) and chemocentryx decoy receptor (CCX CKR). The expression of decoy receptors is mainly restricted in placental cells and endothelial cells of lymphatic afferent vessels in skin, gut and lung.12–14 THE CHEMOKINE NETWORK AT THE MATERNAL–FETAL INTERFACE After the blastocyst hatches from the zona pellucida and adheres to the endometrium during the onset of the implantation window, trophoblast cells proliferate and differentiate into cytotrophoblast and syncytiotrophoblast, resulting in the formation of anchoring chorionic villous. Highly invasive c (...truncated)