The maternal immune system has a profound impact on the progression and outcome of pregnancy and the health of offspring after birth. To test the hypothesis that inflammation in the peri-conception phase exerts adverse impacts on reproductive outcome, we investigated the effects of viral mimetic poly I:C-induced inflammation at conception on fetal development and offspring immune phenotypes.
Using C57Bl/6 mice mated with C57Bl/6 males, we induced mild systemic inflammation by administration of 10 mg/kg poly I:C i.p. on gestational days (gd) 0.5 and 2.5 and mice were analysed at various time points for immune and reproductive outcomes. Poly I:C treatment instigated changes in the relative expression of inflammatory cytokines in the endometrium on gd3.5: Ifny, Il6 and Tnfa were increased ~3-fold, while Cxcl10 and Il10 were elevated ~6-fold (all p<0.001). Flow cytometry on gd3.5 revealed a 75% reduction (p<0.001) in uterine natural killer (uNK) cells. Analysis of decidual spiral arteries by Masson’s trichrome staining in mice killed on gd10.5 revealed a decreased lumen area (p<0.001) and increased vessel-to-lumen area ratio (p<0.001). On gd17.5, fetuses gestated in poly I:C-treated dams were growth-restricted and weighed ~18.5% less than PBS controls (p<0.001). Placental weight was increased (p=0.004) and fetal-to-placental weight ratios were decreased by 32.5% (p<0.001), indicative of placental insufficiency.
After birth, male and female offspring of poly I:C-treated dams exhibited catch-up growth, weighing ~5% more than control offspring (p<0.01). Interestingly, females, but not males, had fewer (~10%) T regulatory (Treg) cells in mesenteric lymph nodes (mLNs) (p=0.029) and impaired expansion of Treg cells in both the spleen (p=0.006) and mLNs (p=0.005) after administration of LPS (10 µg). These findings demonstrate that activation of viral-associated inflammatory pathways in the peri-implantation period affects uNK cells to impair decidual vessel remodelling and placental efficiency, compromising fetal growth and consequently programming altered offspring phenotypes after birth.