People, dogs and about 4,000 other species of placental mammal are distinguished by the ability to nurture a fetus within the body for extended periods of time. This vital adaptation permits the slow development of big brains. Now, a study of gene expression in early pregnancy, when the embryo implants in the uterus, suggests that placental mammals evolved the ability to turn an inflammatory attack on the embryo into an advantage.
“Implantation looks like inflammation because it came from inflammation,” says Arun Chavan, an evolutionary biologist at Yale University in New Haven, Connecticut. He presented the findings on 5 January at the Society for Integrative and Comparative Biology meeting in San Francisco, California. “We did this study to learn how it became an implantation process instead.”
Evolutionary biologists think that ancient mammals laid eggs, as platypuses do today. Marsupials, including opossums and kangaroos, evolved later: their fetuses hatch from a shelled egg within the mother before being expelled from her body shortly after. But that initial hatching seems to fire up the immune system. In a report last July in Proceedings of the National Academy of Sciences, Chavan and his colleagues showed that a suite of inflammatory genes turn on as an opossum (Monodelphis domestica) fetus leaves the egg and clings to the uterine lining1. Previous studies in placental mammals have also shown signs of an immune response when the embryo latches on to the uterus.
But in placental mammals, the embryo does not simply cling to the uterus. Rather, it destroys the uterine lining as it invades the tissue, triggering a flood of inflammatory proteins. During infection and injury, these proteins normally fight invaders and repair wounds. Some of these proteins could be detrimental to a budding life form, but studies suggest that inflammation is necessary for an embryo. For instance, women who take anti-inflammatory drugs in the earliest days of pregnancy have a higher risk of miscarriage because the embryo does not successfully implant in the uterus2. And reproductive biologists argue that certain aspects of inflammation, such as the growth of new blood vessels, help the developing embryo to get the oxygen and nutrients it needs.
Facing the fire
To find out how placental mammals are able to withstand the protein assault in these early days, Chavan analysed the inflammatory response in three of these species: the rabbit (Oryctolagus cuniculus), armadillo (Dasypus novemcinctus) and a hedgehog-like animal called a tenrec (Echinops telfairi). An inflammatory protein, interleukin-17, that had been present in high levels in the opossum seemed to be inactive in the placental mammals — as if it had been switched off. The protein normally beckons white blood cells that kill invaders by digesting them or destroying them with enzymes. “It’s probably important to shut those down before they can damage the embryo,” Chavan says.
His preliminary studies found that cells lining the uterus of placental mammals suppress the production of interleukin-17. Other aspects of the inflammatory response subside later in pregnancy, although it’s unclear what triggers this. The results suggest that placental mammals have fine-tuned inflammation over the course of pregnancy so that it waxes and wanes. “Mammals have figured out a way to keep some aspects of the inflammatory process that are favourable to the fetus, but stop the destructive parts of the response,” says Gunter Wagner, an evolutionary biologist at Yale and the senior investigator on the studies.
The findings are fascinating, says Gil Mor, a reproductive immunologist at Yale. He hopes they will yield details that ultimately help clinicians to reduce miscarriages and improve implantation rates for women undergoing in vitro fertilization. Although inflammation appears to be necessary during implantation, it’s a leading cause of miscarriage and preterm birth in the second and third trimesters. “We need to find ways to switch from pro-inflammatory to anti-inflammatory states so that women can keep their babies,” Mor says.
Updates & Corrections
Correction 10 January 2018: A previous version of this story stated that researchers included hedgehogs in their study, when in fact they looked at an animal called a lesser hedgehog tenrec. The piece has been corrected to reflect this.
Griffith, O. W. et al. Proc. Natl Acad. Sci. USA 114, E6566–E6575 (2017).
Li, D.-K., Liu, L. & Odouli, R. Br. Med. J. 327, 368 (2003).