Dudley JS, Renfree MB, Wagner GP, & Griffith OW. 2024.
PNAS 121 (42) e2310047121, doi.org/10.1073/pnas.2310047121 , published online 8 October 2024

Significance

Our data suggest that moderation of the inflammatory reaction to embryo attachment allows for extension of pregnancy in mammals. The ancestor of all mammals likely experienced an ancestral inflammatory reaction in response to embryo attachment. In contrast, eutherians and some marsupials, such as macropodids, have an extended period of fetal–maternal contact. During this period of placentation many inflammatory genes are silenced while a few others are still expressed. This moderated expression of inflammatory genes suggests that inflammatory mediators were coopted into establishing and maintaining the placenta. This challenges the perspective of inflammation as being detrimental to pregnancy, instead suggesting that fetal–maternal interactions are based on a modified inflammation response necessary for maintaining pregnancy over an extensive period of time.

Abstract

In the first live-bearing mammals, pregnancy was likely short and ended with a brief period of inflammatory maternal–fetal interaction. This mode of reproduction has been retained in many marsupials. While inflammation is key to successful implantation in eutherians, a key innovation in eutherians is the ability to switch off this inflammation after it has been initiated. This extended period, in which inflammation is suppressed, likely allowed for an extended period of placentation. Extended placentation has evolved independently in one lineage of marsupials, the macropodids (wallabies and kangaroos), with placentation lasting beyond the 2 to 4 d seen in other marsupial taxa, which allows us to investigate the role of inflammation response after attachment in the extension of placentation in mammals. By comparing gene expression changes at attachment in three marsupial species, the tammar wallaby, opossum, and fat-tailed dunnart, we show that inflammatory attachment is an ancestral feature of marsupial implantation. In contrast to eutherians, where attachment-related (quasi-) inflammatory reaction is even involved in epitheliochorial placentation (e.g., pig), this study found no evidence of a distinct attachment-related reaction in wallabies. Instead, only a small number of inflammatory genes are expressed at distinct points of gestation, including IL6 before attachment, LIF throughout placentation, and prostaglandins before birth. During parturition, a more distinct inflammatory reaction is detectable, likely involved in precipitating the parturition cascade similar to eutherians. We suggest that in wallaby, extended gestation became possible by avoiding an inflammatory attachment reaction, which is a different strategy than seen in eutherians.