Maternal Decidual Macrophages Inhibit NK Cell Killing of Invasive Cytotrophoblasts During Human Pregnancy

ArticleinBiology of Reproduction 88(6) · April 2013with8 Reads
DOI: 10.1095/biolreprod.112.099465 · Source: PubMed
Human pregnancy is an immunological paradox. Semi-allogeneic (fetal) placental cells (extravillous cytotrophoblasts; CTBs) invade the uterine lining (decidua), which contains a unique decidual Natural Killer (dNK) cell population, identified by the cell-surface phenotype CD56(bright)CD16(-)CD3(-) and CD14(+) CD206(+) macrophages (dMac). Previous reports suggested that human dNK cells are not a threat to the feto-placental unit because they are anergic. In contrast, here we showed that purified and exogenously stimulated dNK cells are capable killers of cellular targets, including semi-allogeneic CTBs. However, dMacs in the decidual leukocyte (DL) population restrained dNK killing through a Transforming Growth Factor (TGF)-β1-dependent mechanism. Our findings support a new model whereby dNK cells, capable of killing CTBs, are prevented from doing so by neighboring macrophages, thus protecting the fetal cells from NK cell attack. We speculate that this mechanism would inhibit dNK cell-mediated killing, even in conditions where high levels of cytokines may stimulate dNK cells, which could pose a threat to the developing placenta.
    • "Contact interactions mediated by receptor–ligand interactions are also recognized between monocytes/macrophages and NK cells, often in the context of enhancing NK cell responses to tumors or microbial pathogens [62]. Interactions between these lineages have not been well studied in either mouse or human decidua, but it is postulated that they dampen uNK cell cytotoxicity [55, 56, 63] . The recent documentation of trogocytosis by human uNK cells [64] enlarges the scope of potential outcomes for uNK cells that may result from interactions with other cell types. "
    Article · Jun 2016
    • "In contrast, M2 macrophages express mannose and scavenger receptors, produce anti-inflammatory cytokines including IL-10 and TGF-β, participate in tissue remodeling, maintain tissue homeostasis, and direct Th2 responses [17, 18]. Although the exact roles of decidual macrophages are not fully defined, studies have demonstrated that these cells are involved in a variety of processes including remodeling of uterine arteries, regulation of trophoblast implantation, immune modulation, promotion of immune tolerance to the semi-allogeneic fetus, and initiation of parturition19202122. While human decidual macrophages are certainly important to the maintenance of pregnancy, an excess of macrophages in the decidua induces EVT cell apoptosis and limits their invasion of spiral arteries [23]. "
    [Show abstract] [Hide abstract] ABSTRACT: It has been shown that adverse obstetrical outcomes such as pre-eclampsia and intrauterine growth retardation (IUGR) correlate with maternal infection. In this study, we investigated mechanisms involved in infection-associated abnormalities in cytotrophoblast function. Primary human first trimester cytotrophoblast cells were isolated and treated with lipopolysaccharide (LPS). Levels of the cytokines and chemokines were measured and cytotrophoblast invasion was investigated. In addition, first trimester decidual macrophages were isolated and treated with the conditioned medium (CM) from LPS-treated cytotrophoblast cells, and macrophage migration was assessed. Co-culturing decidual macrophages with cytotrophoblast cells was conducted to investigate macrophage costimulatory molecule and receptor expression and intracellular cytokine production. We found that LPS exposure increased cytotrophoblast production of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and chemokines IL-8, macrophage inflammatory protein (MIP)-1α and CXCL12 in a dose-dependent manner. In addition, LPS decreased cytotrophoblast invasion, and its effect was Toll-like receptor 4 (TLR4)-dependent and partly TNF-α-dependent. CM from LPS-stimulated cytotrophoblast cells increased decidual macrophage migration and this effect was partly TLR4-dependent. Furthermore, co-culturing decidual macrophages with LPS-exposed cytotrophoblast cells up-regulated macrophage CD80 and CD86 expression and intracellular TNF-α and IL-12p40 production, while down-regulating macrophage CD206 and CD209 expression and intracellular IL-10 secretion. LPS-stimulated macrophages also inhibited cytotrophoblast invasion. In conclusion, our results indicate that LPS can increase cytotrophoblast secretion of pro-inflammatory cytokines and chemokines and inhibit cytotrophoblast invasion. In addition, LPS-stimulated cytotrophoblast cells increase decidual macrophage migration and transform decidual macrophages from an anti-inflammatory M2 phenotype into a pro-inflammatory M1 phenotype.
    Full-text · Article · Dec 2015
    • "Only a small proportion of freshly isolated CD56 + uNK express the degranulation marker CD107 (also known as lysosomal-associated membrane protein 1; LAMP1), the most abundant membrane glycoprotein of lytic granules, in response to HLA-I negative 721.122 cells (Apps et al. 2011b). The low level expression of CD107 by uNK cells may be a strategic plan adopted from pNK to minimize degranulation-associated apoptosis (Cohnen et al. 2013). In a redirected killing assay using mouse mastocytoma P815 cells, the engagement of NKp46 greatly improved the degranulation and cytotoxic capacity of human uNK cells (El Costa et al. 2008). "
    [Show abstract] [Hide abstract] ABSTRACT: The maternal-fetal interface undergoes dynamic changes that promote successful development of the embryo/fetal allograft during pregnancy. This immune privilege of the conceptus is mediated through local and systemic cellular responses. In species in which endometrial decidualization accompanies pregnancy, unique immune cell niches are found. Many studies have addressed the enigmatic roles of uterine (u)NK cells as killers and helpers because they are frequently found in the uterine lining and decidua of normal and pathological pregnancies. Accumulating evidence indicates that uNK cells are induced and transformed by sensing signals within their microenvironment to both protect the mother from the fetal allograft and support the fetus during its development. Here, we review the mechanisms that modulate these functions of uNK cells during pregnancy. We suggest that uNK cells must be tightly regulated in order to serve these two roles and support a healthy pregnancy.
    Full-text · Article · Nov 2015
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