1017: Gene expression profiling fetal Hofbauer cells and maternal intervillous macrophages

Abstract

The diverse functional phenotypes of macrophages are broadly divided into two classes: a pro-inflammatory M1- type, and an anti-inflammatory, M2-type. Fetal Hofbauer cells (HBC) and maternal intervillous macrophages (MIM) are macrophages found in the placental villi. HBC have been described as being primarily of the M2 immunomodulatory phenotype; little is known regarding the molecular phenotype of MIM. Here, using an exploratory- and hypothesis-based approach, we investigated the transcriptional profiles of HBC and MIM in normal pregnancy. This is a case control study of women with normal deliveries at term. Paired HBC and MIM were isolated from six placentas immediately after delivery. Total RNA was extracted for RNA sequencing (n=12). Data were processed via DESeq2, and fixed effects linear models were applied to define differentially expressed (DE) genes based on cell origin (p<0.001; absolute fold change ≥3). Functional enrichment analysis of DE genes was performed using DAVID. We evaluated the mRNA expression levels of 50 common macrophage markers related to M1/M2 activation in HBC and MIM. Between HBC and MIM, 2,137 DE genes were identified. Within this subset, 957 and 1,080 genes were more highly expressed in HBC (HBC-up) and MIMs (MIM-up), respectively. HBC-up genes were enriched for inflammatory response, leukocyte activation, and vasculature development. MIM-up genes were overrepresented by pathways related to female pregnancy and innate immune response in mucosa. Expression profiles of macrophage markers in HBCs and MIMs showed diverse M1- and M2-type signatures. In general, these genes were expressed at higher levels in HBC as compared to MIM. In particular, ten markers were significantly DE between HBC and MIM, including IL8, a pro-inflammatory cytokine, which also was the most highly expressed gene in both cell types. Fetal HBCs and MIMs have highly divergent transcriptional signatures, reflecting their distinct origins. These differences between fetal and maternal macrophage activation states could potentially drive unique responses to infection and inflammatory stressors. Fetal HBCs also strongly express genes associated with M1 macrophage responses, suggesting more phenotypic diversity than previously described.