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Regulatory role of multinucleated giant cells derived from placental CD14+ macrophages: Pathophysiological implications

ABSTRACT: The role of placental macrophages is largely ignored in the success of pregnancy. We found that CD14+ macrophages purified from at-term placentas spontaneously matured into multinucleated giant cells (MGCs). MGCs lost the expression of CD14 and co-inhibitory molecules, such as Programmed cell Death-Ligands 1 and 2. Although MGCs kept phagocytosis and property to produce ROS, their inflammatory potential measured by TNF/IL-10 imbalance and activation of p38 MAPK and NF-κB was blunted without being associated with M2 phenotype. The investigation of gene expression revealed the enrichment with categories related to inflammation, apoptosis and canonical functions of macrophages in MGCs. Whereas most of the genes associated with inflammation and immune responses were down-modulated, those such as VEGFC or associated with matrix remodeling were specifically up-regulated in MGCs. Importantly, we found that patients with preeclampsia or chorioamnionitis, two inflammatory and infectious pathologies, respectively, that affect placentas, were unable to generate MGCs. Taken together, these results suggest that MGCs represent a new way to regulate the inflammatory and cytocidal activity of placental macrophages in a context that imposes contradictory constraints, such as semi-allograft acceptance and defense against aggression. The dysregulation of MGC formation may be associated with placental inflammatory and infectious pathologies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE38747 | GEO | 2014/01/07

SECONDARY ACCESSION(S): PRJNA168560

REPOSITORIES: GEO

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Project description:A major population of placenta macrophages represented throughout the pregnancy consists of CD14+ macrophages, but their characteristics remain badly understood. Here we purified from placentas at term CD14+ macrophages using positive selection. The phenotyping of CD14+ macrophages performed using flow cytometry revealed that placenta CD14+ macrophages expressed a series of markers distinct of those of circulating monocytes monocyte-derived macrophages. Placenta CD14+ macrophages spontaneously matured in multinucleated giant cells (MGCs) as demonstrated by size, number of nuclei display and specific cytoskeleton organization. Placenta CD14+ macrophages and MGCs were phagocytic cells but the potential of MGCs to mount an inflammatory response was lower than that of their precursors. Placenta CD14+ macrophages and MGCs stimulated with interferon and interleukin-4 were not polarized into typical M1 or M2 profiles. Placenta macrophages exhibited specific activation transcriptional programs. Indeed, principal component analysis and hierarchical clustering show that placental macrophages formed a distinct group from circulating monocytes and monocyte-derived macrophages. Among placenta macrophages, it was also possible to distinguish CD14+ macrophages and MGCs. In addition, networks based on gene interactions were clearly different in CD14+ macrophages and MGCs. Finally, the microenvironment of placenta CD14+ macrophages governs their differentiation into MGCs because CD14+ macrophages incubated with trophoblasts exhibited exarcerbated characteristics of MGCs and because the co-incubation of circulating monocytes from working women with trophoblast supernatants resulted into the formation of MGCs whereas monocytes from non-pregnant women incubated with trophoblast supernatants did not differentiate into MGCs. Taken together, these results clearly demonstrated specific feaures of placenta CD14+ macrophages. Three replicates of each of the following: 1. Placental macrophages just after isolation (CD14+ macrophages) 2. Placental macrophages after 9 days in culture (MGCs) 3. CD14+ cells isolated from PBMC which are extracted from the whole human blood of healthy donors (Monocytes) 4. Macrophages derived from monocytes (MDMs)

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Regulatory role of multinucleated giant cells derived from placental CD14+ macrophages: Pathophysiological implications

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