ABSTRACT: Activation of the maternal immune system during pregnancy affects fetal development, which can increase in postnatal susceptibility to a range of diseases, including cardiovascular, metabolic and psychiatric disorders. During maternal immune activation (MIA), the maternal body must balance its ressources between mounting an immune response and investing resources into continued metabolism and growth, essentials for survival of the fetus and a successful pregnancy. How the placenta responds to MIA over time and how it can protect the fetus is not well understood, and neither are the fetal consequences of MIA. Here, we characterised the response to acute maternal lung inflammation across time in maternal and fetal organs, using a combination of omics, imaging and integrative computational analyses. We found that the placenta, unlike other maternal organs, did not react by a typical innate immune response, but instead induced genes associated with increased tissue integrity, likely to prevent fetal exposure to potential infections, and simultaneously reduced expression of growth-associated genes. Subsequently, a return to homeostasis was observed, with heightened expression of biosynthesis and endoplasmic reticulum (ER) stress genes. These responses likely protect the fetus from inflammation, as we observed no immune response in the fetal liver transcriptome. Instead, we observed metabolic adaptations in the fetus, including a release of docosahexaenoic acid (DHA) carrying metabolites, including triglyceride and phosphatidylcholine. Notably, DHA is crucial for fetal brain development. This metabolic response is likely a combination of the placental MIA response and temporary maternal fasting, caused by MIA-induced fever and lack of nutrient intake. Our study shows, for the first time, the integrated temporal and systemic response to LPS in lungs across maternal and fetal organs
