Fetal inflammatory signals regulate maternal investment in a pregnant marsupial

Marsupial pregnancy is strikingly short: placental attachment in the gray short-tailed opossum Monodelphis domestica lasts only two days. This brevity has been attributed to a maternal immune response to fetal contact which only eutherian mammals have evolved mechanisms to tolerate. The attachment period is characterized by a spike in inflammatory signaling, development of an expanded uterine capillary network, and exponential fetal growth. Several inflammatory cytokines, including interleukin-1A (IL-1A) and interleukin-6 (IL-6), are produced primarily by fetal cells. We hypothesized that placental cytokines function as solicitation signals that increase maternal investment. To test this, we treated pregnant opossums with inhibitors of IL-1 and IL-6 during the rapid growth phase. Inhibition of IL-1 and IL-6 signaling significantly increased average biomass per fetus (+12% and +10%), and as such these signals impose costs, rather than direct benefits, to intrauterine growth. However, uninhibited controls showed greater surviving litter sizes than IL-1-inhibited animals, suggesting that IL-1A promotes offspring survival. Single-cell transcriptomes reveal that maternal vascular endothelial cells, perivascular cells, and fibroblasts are the primary targets of fetal IL-1A, and maternal cells simultaneously upregulate antagonists IL1R2 and IL1RN, suggesting resistance to fetal signaling. Placental transcriptomics reveals that the cytokine surge is restricted to the final day of pregnancy when placental cells fuse to form syncytial knots, and that these cells produce additional vasomodulatory signals including a truncated isoform of VEGFA. Maternal cells, in contrast, increase production of functional antagonists IL1R2 and IL1RN, suggesting resistance to fetal signals. We propose that marsupials co-opted inflammatory signals to perform a novel function promoting fetal survival through maternal vascular remodeling.