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

Abstract

BackgroundAlthough uterine macrophages are thought to play an important regulatory role at the maternal-fetal interface, their global gene expression profile is not known.Methodology/Principal FindingsUsing 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.Conclusions/SignificanceThe 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.

Immunological role of vitamin D at the maternal–fetal interface

“…Comparison between first-and second-trimester leukocyte populations has recently found that, although there was a significant decline in total macrophage numbers, a CD163 C CD206 C subset designating alternatively activated pro-tolerogenic M2-like macrophages concomitantly increased (Kwan et al 2014). Microarray gene expression analysis of human 1st-trimester decidua-derived macrophages has also revealed gene expression patterns associated with M1 and M2 macrophages (Gustafsson et al 2008). In addition to their enhanced immune-modulatory potential, decidual macrophages also demonstrated a higher proliferative and tissue remodelling capacity, when compared with their peripheral blood counterparts (Gustafsson et al 2008).…”

“…Microarray gene expression analysis of human 1st-trimester decidua-derived macrophages has also revealed gene expression patterns associated with M1 and M2 macrophages (Gustafsson et al 2008). In addition to their enhanced immune-modulatory potential, decidual macrophages also demonstrated a higher proliferative and tissue remodelling capacity, when compared with their peripheral blood counterparts (Gustafsson et al 2008). In the context of adverse pregnancy, elevated serum concentrations of IL12 (which augment the production of inflammatory cytokines) have also been measured in the peripheral blood of women with pre-eclampsia (PET) (Saito et al 1999).…”

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…19,20 Moreover, IL-10 is noted for its abilities to inhibit Mw proliferation by activating Stat3 33 and Trophoblast-mediated deactivation of macrophages A Dallagi et al to suppress IFN-c-mediated functions of Mws by blocking Stat1 activation. 34 In the pregnant human uterus, IL-10 is produced in large amounts by both the syncytiotrophoblast and the decidual Mws, 9,10,28,29 while LIF is highly expressed by decidual Mws and uNK cells. 35 On the other hand, the IL-10 receptor is constitutively expressed on placental trophoblasts 28,29 and decidual Mws are known to be highly responsive to IL-10.…”

Macrophages at the Fetal–Maternal Interface Express Markers of Alternative Activation and Are Induced by M-CSF and IL-10

“…It is therefore not surprising that decidual Mf in humans (22,(29)(30)(31)(32)(33), as well as in other species (34,35), seem to acquire an M2 phenotype, which may contribute to both remodeling of the endometrium and the tolerant milieu that is required for fetal acceptance. However, despite the important roles of Mf at the fetal-maternal interface, surprisingly little is known about the factors that regulate the differentiation and polarization of Mf in the decidua.…”

“…Decidual Mf and the in vitro Mf were phenotypically characterized to evaluate their similarity. The markers included the mannose receptor (CD206), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN, CD209), and ICAM-3, all being differentially regulated at the gene level in decidual Mf (33), as well as the M2-associated scavenger receptor (CD163) and neuropilin-1 (NRP-1, CD304), not previously described in Mf from early human pregnancy (36,37). A set of secreted cytokines and chemokines (IL-1b, IL-6, IL-10, TNF, and CCL4) was also analyzed to characterize the Mf populations.…”