Gene Expression Profiling of Human Decidual Macrophages: Evidence for Immunosuppressive Phenotype

Division of Clinical Immunology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, University Hospital, Linköping, Sweden.
PLoS ONE (Impact Factor: 3.53). 02/2008; 3(4):e2078. DOI: 10.1371/journal.pone.0002078
Source: PubMed

ABSTRACT Although uterine macrophages are thought to play an important regulatory role at the maternal-fetal interface, their global gene expression profile is not known.
Using micro-array comprising approximately 14,000 genes, the gene expression pattern of human first trimester decidual CD14+ monocytes/macrophages was characterized and compared with the expression profile of the corresponding cells in blood. Some of the key findings were confirmed by real time PCR or by secreted protein. A unique gene expression pattern intrinsic of first trimester decidual CD14+ cells was demonstrated. A large number of regulated genes were functionally related to immunomodulation and tissue remodelling, corroborating polarization patterns of differentiated macrophages mainly of the alternatively activated M2 phenotype. These include known M2 markers such as CCL-18, CD209, insulin-like growth factor (IGF)-1, mannose receptor c type (MRC)-1 and fibronectin-1. Further, the selective up-regulation of triggering receptor expressed on myeloid cells (TREM)-2, alpha-2-macroglobulin (A2M) and prostaglandin D2 synthase (PGDS) provides new insights into the regulatory function of decidual macrophages in pregnancy that may have implications in pregnancy complications.
The molecular characterization of decidual macrophages presents a unique transcriptional profile replete with important components for fetal immunoprotection and provides several clues for further studies of these cells.

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    ABSTRACT: Extravillous trophoblasts (EVTs) play a central role in educating maternal leukocytes, endometrial stromal and endothelial cells to generate a receptive decidual microenvironment tailored to accept the semi-allogeneic fetus. HLA-G, a non-classical HLA class I molecule endowed with immune-regulatory functions, is primarily expressed on EVTs lining the placenta and on the naturally occurring tolerogenic dendritic cells, named DC-10, which are enriched in the human first trimester decidua. Decidual DC-10 are involved in HLA-G-mediated tolerance at the maternal-fetal interface. EVTs not only establish a tolerogenic microenvironment through the interaction with maternal innate and adaptive cells but also orchestrate placenta vascular and tissue remodeling, leading to a successful pregnancy. Here, we discuss the potential implications of the HLA-G-mediated cross-talk among the cells present at the maternal-fetal interface, and its role in maintaining a positive relationship between the mother and the fetus.
    Frontiers in Immunology 01/2015; 6:128. DOI:10.3389/fimmu.2015.00128
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    ABSTRACT: The establishment of pregnancy requires the co-ordinated implantation of the embryo into the receptive decidua, placentation, trophoblast invasion of the maternal decidua and myometrium in addition to remodelling of the uterine spiral arteries. Failure of any of these steps can lead to a range of pregnancy complications, including miscarriage, pre-eclampsia, fetal growth restriction, placenta accreta and pre-term birth. Cytokines are small multifunctional proteins often derived from leucocytes and have primarily been described through their immunomodulatory actions. The maternal-fetal interface is considered to be immunosuppressed to allow development of the semi-allogeneic placental fetal unit. However, cytokine profiles of the decidua and different decidual cell types suggest that the in vivo situation might be more complex. Data suggest that decidual-derived cytokines not only play roles in immunosuppression, but also in other aspects of the establishment of pregnancy, including the regulation of trophoblast invasion and spiral artery remodelling. This review focuses on the potential role of decidua-derived cytokines in the aetiology of unexplained spontaneous miscarriage. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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    ABSTRACT: A successful pregnancy requires that the maternal immune system adapts to tolerate the semi-allogeneic fetal-placental unit. This adaptation mainly occurs locally, i.e. at the fetal-maternal interface, where fetal-derived tissues come into close contact with maternal cells in the uterine endometrium (called decidua during pregnancy). Macrophages and regulatory T (Treg) cells are maternal immune cells that are enriched in the decidua and they likely play a central role in promoting fetal tolerance. However, the precise function of decidual macrophages and the factors regulating both macrophages and Treg cells in humans are unknown. The aim of this thesis was to characterize the phenotype and function of decidual macrophages from first trimester human pregnancy and to identify factors responsible for inducing tolerogenic properties in both decidual macrophages and Treg cells. CD14+ decidual macrophages showed characteristics of immune suppressive or homeostatic macrophages (expression of CD163, CD206 and CD209), mainly produced immunosuppressive cytokines, like IL-10 and IL-35, while levels of inflammatory cytokines, for instance IL-12 and IL-23, were low. Decidual macrophages also induced the expansion of CD25highFoxp3+ Treg cells, but not of Th1, Th2 and Th17 cells, in vitro. In addition, decidual macrophages preferentially secreted the monocyte- and Treg cell-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. These results suggest that decidual macrophages contribute to create the unique decidual cell composition and a tolerogenic immune environment that is compatible with fetal development. Further, by comparing decidual macrophages with different in vitro macrophage subsets, we showed that M-CSF and IL-10, but not GM-CSF, Th1 or Th2 stimuli, induced macrophages that resemble decidual macrophages in terms of cell surface marker expression, cytokine and chemokine production and gene expression profile. First trimester placental tissue, in particular placental trophoblast cells, was identified as an important source of M-CSF and IL-10. We also demonstrated that human fetal-derived placental tissue can induce the characteristics of decidual macrophages (CD163+CD206+CD209+IL-10+CCL18+) and the selective expansion of functionally suppressive CD25highFoxp3+ Treg cells, the latter partly mediated through IL-10, TGF-β and TRAIL. The placenta also limited activation of Th cells, for instance by generally reduced cytokine production. Our data show that the placenta has a unique ability to induce tolerogenic immune cells with a reduced inflammatory potential, which is essential for maintaining tissue integrity and preventing inflammation-induced fetal loss.

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