Abstract
In situ production and metabolism of all-trans retinoic acid (RA) in decidual tissue are critically important for endometrial stromal differentiation, embryo implantation, and healthy placentation. However, the cellular source(s) of RA in this tissue has yet to be determined. To identify the primary RA-producing cells in human term decidua, we isolated cells from decidua basalis of delivered placenta and quantified cellular retinal dehydrogenase (RALDH) activity, a major biosynthetic enzyme whose activity determines the synthesis of RA from retinol, using an Aldefluor assay and flow cytometry. RA production in decidual tissue and sorted cell subpopulations was evaluated by liquid chromatography-tandem mass spectrometry. CD14+ cells (macrophages/monocytes) showed > 4-fold higher RALDH activity than stromal cells (CD10+), T cells (CD3+), or non-T lymphocytes (CD3-negative). CD11c+ cells that did not co-express CD14 showed about one-third the RALDH activity of their CD14 co-expressing counterparts. The highest RALDH activity was found in "alternatively activated" M2 macrophages delineated by the simultaneous expression of CD14 and CD163. The greater RA synthesizing capacity of M2 versus CD14+CD163-ve (M1) cells was confirmed by direct quantitation of RA biosynthesis from retinol. RA levels in whole decidua were correlated with M2 cell density but not with stromal cell (CD10+) number, the major cell type comprising the decidua. These results identified M2 monocyte/macrophages as the primary source of RA in human term decidua. This finding may have implications for certain pregnancy complications that are known to be associated with reduced numbers of decidual M2 cells.
Highlights
Vitamin A, through its active metabolite all-trans retinoic acid (RA), is essential to the homeostasis of mucosal tissue and regulation of innate adaptive immunity [1,2,3,4]
Our analysis showed a close approximation to a linear regression model of decidual tissue RA concentration to the corresponding M2 cell density (Fig. 5), supporting the contention that these cells are the predominant decidual source of RA biosynthesis
We determined that decidual CD10+ stromal cells are a lesser source of RA production on a per cell basis, we considered the possibility that, since these cells are numerically abundant, they may contribute to overall RA levels in bulk decidua tissue
Summary
Vitamin A, through its active metabolite all-trans retinoic acid (RA), is essential to the homeostasis of mucosal tissue and regulation of innate adaptive immunity [1,2,3,4]. In this regard, the most extensively studied compartment is the gastro-intestinal tract (GIT) where tolerance to a plethora of foreign antigens (e.g. commensal microorganisms) is mediated by regulatory T cells (Tregs) that are in part regulated by RA produced and secreted by specialized dendritic cells [5,6]. The density of this RA-regulated cell population is reduced in various pregnancy-related syndromes associated with a proinflammatory phenotype, including fetal growth restriction, pre-term labor, and preeclampsia [12,13,14]
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