The Integrative Roles of Chemokines at the Maternal–Fetal Interface in Early Pregnancy
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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 linked to some pregnancy failures, such as miscarriage, pre- The intimate association between maternal and placental tis- eclampsia, fetal growth restriction and so on. The chemo- sues elicits an interesting immunological paradox. Placental kine/chemokine receptor interactions play roles in almost all tissue contains paternal antigens, but under normal circum- facets of maternal–fetal crosstalk. In this review, we highlight stances, the allogeneic fetus and placenta are not attacked by the the contribution of chemokines and their receptors at the maternal immune system. Interestingly, this tolerance to fetal maternal–fetal interface to the maintenance of normal preg- antigens occurs in the presence of a large number of maternal nancy, especially to maternal–fetal tolerance and to placenta- leukocytes, almost all of which are members of the innate tion. Since normal pregnancy is a model of natural immune immune system. There is a delicate crosstalk and collaboration tolerance, pregnancy research may assist in the broader under- between fetus-derived trophoblast cells and maternally-derived standing of tumor immunology and of transplantation cells during normal pregnancy to establish a unique maternal– immunology. fetal immune milieu that contributes to embryo survival and development in the uterus until parturition. Dysfunction in the THE CHEMOKINE FAMILY interactions of trophoblasts and maternally-derived cells and The chemokines constitute a superfamily of small chemotactic dysregulation of maternal–fetal immune tolerance are highly 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 1M-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: [email protected] 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: [email protected] 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 trophoblasts, maternal DSCs and DICs are the main compo- effects through G protein-coupled receptors.2 Based on their nents at the maternal–fetal interface. Figure 1 describes the structural motif, including the number and position of two dynamic formation process of maternal–fetal interface in early conserved cysteine residues, chemokines are classified into sub- human pregnancy. Functional chemokines and their receptors families: the CXC, CC, CX3C and C groups or the a, b, c and d are widely expressed at the maternal–fetal interface, and play a subfamilies. Chemokine receptors are also divided into four pivotal role in this intercellular communication. Through corresponding groups.3 One or three amino acids separate Reverse Transcription-Polymerase Chain Reaction (RT-PCR) the first and second cysteines in the CXC and CX3C chemo- assay, our group systematically analyzed the expression of 18 kines, respectively, the two cysteines are adjoining in the CC chemokine receptors at the maternal–fetal interface disclosing subfamily, and the C subfamily lacks the first and pairing third general and differential expression patterns. In primary tropho- conserved cystein residues. The fifth receptor subfamily, CX, blast, we found high levels of CXCR4 and CXCR6 mRNA, mod- reported only in zebrafish lacks the two N-terminal residues, erate expression of CCR1, CCR3, CCR5, CCR8, CCR9, CXCR1, 4 but retains the third and fourth residues. The CXC family can CXCR4, CXCR6, XCR1 and CX3CR1 and no expression of CCR2, be further subdivided by the presence or absence of a conserved CCR6, CCR7, CCR10 and CXCR5.15 In contrast, in human DSCs, ‘Glu-Leu-Arg’ (ELR) subsequence at the NH2 terminus. The CCR2, CCR5 and CCRl0 are highly expressed while CCR1, CCR3, 1 2 ELR family is involved in angiogenesis and the ELR family is CCR4, CCR6, CCR8-9, CXCRl, CXCR4, CXCR6, XCR1 and 5 involved in angiostatic activity. CX3CRl are moderately expressed. CCL2 and CCLl3, the ligands The primary functions of chemokines are the directional of CCR2, and CCL28, the ligand of CCRl0, are also expressed stimulation of immune-cell adhesion and migration into the highly in decidua and DSCs.16 Further studies have shown that infected or inflamed tissue to initiate effective immune res- primary trophoblasts secrete high levels of CXCL12 and CXCL16, ponses. However, chemokine functions are not restricted to while DSCs produce abundant CCL2.15–17 In addition, tropho- chemotaxis but serve many other immune purposes such as blasts secrete CCL24, whereas DSCs express its receptor, CCR3.18 dendritic cell (DC) maturation,6 B-cell antibody class switch- 7 8 These data suggest that a complicated chemokine/chemokine ing, and T-cell activation and differentiation. Chemokines receptor network is present at maternal–fetal interface. are also potent mediators of neoangiogenesis and tumor CXCL14 is a relatively newly-identified chemokine with an growth, invasion, and metastasis,9,10 and play a pivotal role unidentified receptor and undefined function. CXCL14 is in embryogenesis and organ transplantation.11 selectively expressed in early villous cytotrophoblasts and More recently, chemokine receptors with structural features DSCs.19 When villous cytotrophoblasts differentiates into syn- that are inconsistent with a signalling function have been cytiotrophoblast cells, CCR3 and CCR6 become highly described. When ligated, these ‘silent’ (non-signalling) chemo- expressed.20 CCR1 and CCL17 are localized on extravillous kine receptors do not elicit migration or conventional signalling cytotrophoblast cells (EVTs).21,22 CXCR4 and CXCR7 are responses, but regulate inflammatory and immune reactions in expressed during the differentiation process of cytotropho- different ways, such as acting as decoys or scavengers. The blasts towards the invasive phenotype,23 and their ligand availability of chemokines is regulated by three non-signalling CXCL12 is widely expressed in multiple cell types at the mater- decoy receptors: chemokine decoy receptor (D6), Duffy antigen 22 24 receptor for chemokines (DARC) and chemocentryx decoy nal–fetal interface. Invasive EVTs express CX3CR1. As for receptor (CCX CKR). The expression of decoy receptors is the maternal side of the interface, there is widespread expres- mainly restricted in placental cells and endothelial cells of sion of chemokines. On DSCs, these include the ligands CCL2, lymphatic afferent vessels in skin, gut and lung.12–14 CCL4, CCL7, CCL14, CCL16, CCL17, CXCL9, CXCL10, CXCL11, CXCL14 and CX3CL1 and the receptors CCR2, 25–27 THE CHEMOKINE NETWORK AT THE MATERNAL–FETAL CCR3, CCR10, CXCR3 and CXCR4. In addition, CCL2, INTERFACE CCL28 and CX3CL1 are also immunolocalized on the decidual 28,29 After the blastocyst hatches from the zona pellucida and epithelial cells (DECs). CCR3 and CCR4 are expressed on 30,31 adheres to the endometrium during the onset of the implanta- the invading interstitial EVTs. In addition to trophoblasts tion window, trophoblast cells proliferate and differentiate into and DSCs, chemokine receptors are expressed on decidual cytotrophoblast and syncytiotrophoblast, resulting in the