Abstract
Prenatal inflammation negatively affects placental function, subsequently altering fetal development. Pathogen-associated molecular patterns (PAMPs) are used to mimics infections in preclinical models but rarely detected during pregnancy. Our group previously developed an animal model of prenatal exposure to uric acid (endogenous mediator), leading to growth restriction alongside IL-1-driven placental inflammation (Brien et al. in J Immunol 198(1):443–451, 2017). Unlike PAMPs, the postnatal impact of prenatal non-pathogenic inflammation is still poorly understood. Therefore, we investigated the effects of prenatal uric acid exposure on postnatal neurodevelopment and the therapeutic potential of the IL-1 receptor antagonist; IL-1Ra. Uric acid induced growth restriction and placental inflammation, which IL-1Ra protected against. Postnatal evaluation of both structural and functional aspects of the brain revealed developmental changes. Both astrogliosis and microgliosis were observed in the hippocampus and white matter at postnatal day (PND)7 with IL-1Ra being protective. Decreased myelin density was observed at PND21, and reduced amount of neuronal precursor cells was observed in the Dentate Gyrus at PND35. Functionally, motor impairments were observed as evaluated with the increased time to fully turn upward (180 degrees) on the inclined plane and the pups were weaker on the grip strength test. Prenatal exposure to sterile inflammation, mimicking most clinical situation, induced growth restriction with negative impact on neurodevelopment. Targeted anti-inflammatory intervention prenatally could offer a strategy to protect brain development during pregnancy.
Highlights
Prenatal inflammation negatively affects placental function, subsequently altering fetal development
Following up from this work, our objective was to investigate the postnatal impact of prenatal exposure to sterile or non-pathogenic inflammation induced by uric acid, on brain development
Since we previously showed that the placental impact of in utero exposure to uric acid was mediated mainly through the IL-1 pathway as seen by reduced percentage of M30+ apoptotic cells and increased syncytialization with treatment of uric acid crystals (UA) and IL-1 blockers[33], we tested the therapeutic potential of prenatal anti-inflammatory treatment through administration of the IL-1 receptor antagonist (IL-1Ra)
Summary
Prenatal inflammation negatively affects placental function, subsequently altering fetal development. We investigated the effects of prenatal uric acid exposure on postnatal neurodevelopment and the therapeutic potential of the IL-1 receptor antagonist; IL-1Ra. Uric acid induced growth restriction and placental inflammation, which IL-1Ra protected against. Uric acid induced growth restriction and placental inflammation, which IL-1Ra protected against Postnatal evaluation of both structural and functional aspects of the brain revealed developmental changes. Elevated uric acid levels have been shown to be associated with complicated pregnancies such as preeclampsia[34,35,36] In this model, uric acid crystals were injected in the late gestation period in rats, leading to placental inflammation with increased levels of cytokines (e.g. IL-1β, IL-6, TNFα) and immune cells infiltration within the placenta. We observed that uric acid injection at the end of the pregnancy induced fetal growth restriction (FGR)[33]
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