Conceptus attachment coincides with initiation of an anti-inflammatory cytokine profile in the pig endometrium

Abstract Blastocyst implantation is associated with quasi-inflammatory reactions in the endometrium, which are resolved during the establishment of the definitive placenta. Quasi-inflammatory processes have also been documented in pregnant pigs, even though the blastocyst only attaches to, rather than implants into the endometrium. We asked what processes lead to the resolution of attachment-associated inflammation. In wound healing the transition towards an anti-inflammatory state includes the transition from M1 to M2 polarized macrophages. In order to determine whether this scenario applies also to the peri-attachment porcine uterus, we produced a series of bulk transcriptomes spanning days 13 to 25 of gestation. We found slower changes in the transcriptome between D20 and D25 than prior to D20, suggesting a turning point in pregnancy-related endometrial reprogramming. This period corresponds to the firm attachment of trophectoderm to the uterine epithelium and the cessation of IFNG signaling from the blastocyst. We found increased expression of genes implicated in resolution of inflammation and M2 polarization such as ARG1, MRC1, CD86, TGFb1 and IL10, and an increase in expression of HGPD, the enzyme metabolizing prostaglandins. While immunoreactivity for ARG1 was found in putative macrophages, other M2 markers were localized to non-immune cells: MRC1 in fibroblast-like stromal cells, CD86 on trophoblast cells, and IL10 in endometrial epithelia. CD86 undergoes trogocytosis into the luminal epithelium by D25. These results suggest that intrauterine immune regulation is decoupled from that of the rest of the body by engaging non-immune cells as anti-inflammatory mediators during the peri-attachment period of porcine pregnancy.