Abstract
Maintaining the homeostasis of the decidual immune microenvironment at the maternal-fetal interface is essential for reproductive success. Dendritic cells (DCs) are the professional antigen-presenting cells and dominate this balance of immunogenicity and tolerance. Progesterone (P4) is highlighted as the “hormone of pregnancy” in most eutherian mammals because of its regulatory role in immune-endocrine behavior during pregnancy. Recent studies have shown that P4 is associated with the differentiation and function of DCs, however, the underlying mechanisms remain unidentified. In addition, while progress in the field of immunometabolism has highlighted the intimate connections between the metabolism phenotype and the immunogenic or tolerogenic fate of DCs, whether P4 can affect DCs metabolism and thus exert a functional manipulation has not yet been explored. In this study, we acquired human peripheral blood monocyte-derived DCs and conducted RNA sequencing (RNA-seq) on immature DCs (iDCs), P4-treated DCs (pDCs), and mature DCs (mDCs), aiming to comprehensively assess the effects of P4 on DCs. Our results showed pDCs performed a distinct differentially expressed genes (DEGs) profile compared with iDCs or mDCs. Further functional enrichment and weighted gene co-expression network (WGCNA) analysis found that these DEGs were related not only to the cellular components but also to the significant metabolic activities, including mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid metabolism. In addition, these changes may be involved in the activation of various signaling pathways of PI3K/Akt/mTOR, AMPK/PGC1-α, and PPAR-γ. In summary, our work suggested that P4 induced profound metabolic alterations of mitochondrial OXPHOS and fatty acid metabolism in DCs. Our findings may provide new insights into the role of P4 in DCs.
Highlights
To investigate the alterations of human Dendritic cells (DCs) exposed to P4, the morphological features of immature DCs (iDCs), P4-treated DCs (pDCs), and mDCs were observed and photographed on day 7
Our results showed that the genes of mitochondrial complexes II-V were highly expressed in pDCs compared with mDCs, though no significant differences were detected in complex I− NADH ubiquinone oxidoreductase subunit B8 (NDUFB8) (Figure 6A)
We demonstrated significantly increased protein levels of oxidative phosphorylation (OXPHOS) complexes in pDCs compared with mDCs (Figures 6B, C)
Summary
Pregnancy is a complex and highly coordinated event. Immunologically, the embryo is a semi‐allograft that resides in an immune-competent mother, the distinct tolerable microenvironment at the maternal interface provides a guarantee for a successful pregnancy. The underlying mechanisms of maternal-fetal tolerance are multiple including the change of immune cells populations, induction of regulatory T cells, and the shift of Th1 pro-inflammatory to Th2 anti-inflammatory cytokine responses [1, 2]. These alternations are sophisticatedly orchestrated under the immune-endocrine interactions. Studies have emphasized P4 as a communication bridge of endocrine-immune to mediate maternal tolerance to the fetus via acting on a series of decidual immune cells, including natural killer cells, T cells, and dendritic cells (DCs) [10–13]. The effect of P4 on DCs has gained great attention because of its plastic talent in inducing antigen-specific immunity or tolerance at the maternalfetal interface
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