Abstract
BackgroundInfants born preterm due to chorioamnionitis are frequently affected by a fetal inflammatory response syndrome (FIRS) and then by subsequent postnatal infections. FIRS and postnatal systemic inflammatory events independently contribute to poor neurocognitive outcomes of preterm infants. Developmental integrity of the hippocampus is crucial for intact neurocognitive outcomes in preterms and hippocampally dependent behaviors are particularly vulnerable to preterm systemic inflammation. How FIRS modulates the hippocampal immune response to acute postnatal inflammatory events is not well understood.MethodsPrenatal LPS exposed (FIRS) and control neonatal rats received i.p. LPS or saline at postnatal day (P) 5. On P7, immune response was evaluated in the hippocampus of four treatment groups by measuring gene expression of inflammatory mediators and cytosolic and nuclear NFκB pathway proteins. Microglial activation was determined by CD11b+ and Iba1+ immunohistochemistry (IHC) and inflammatory gene expression of isolated microglia. Astrocyte reactivity was measured using Gfap+ IHC.ResultsPostnatal LPS resulted in a robust hippocampal inflammatory response. In contrast, FIRS induced by prenatal LPS attenuated the response to postnatal LPS exposure, evidenced by decreased gene expression of inflammatory mediators, decreased nuclear NFκB p65 protein, and fewer activated CD11b+ and Iba1+ microglia. Isolated microglia demonstrated inflammatory gene upregulation to postnatal LPS without evidence of immune tolerance by prenatal LPS.ConclusionPrenatal LPS exposure induced immune tolerance to subsequent postnatal LPS exposure in the hippocampus. Microglia demonstrate a robust inflammatory response to postnatal LPS, but only a partial immune tolerance response.
Highlights
Infants born preterm due to chorioamnionitis are frequently affected by a fetal inflammatory response syndrome (FIRS) and by subsequent postnatal infections
We previously studied the inflammatory response of the hippocampus to a prenatal inflammatory event in a rat model of FIRS and reported persistent postnatal altered expression of proinflammatory genes and microglial activation associated with gray matter dysregulation [26]
We previously showed no difference in survival between neonatal animals exposed to prenatal LPS or saline [26]
Summary
Infants born preterm due to chorioamnionitis are frequently affected by a fetal inflammatory response syndrome (FIRS) and by subsequent postnatal infections. FIRS and postnatal systemic inflammatory events independently contribute to poor neurocognitive outcomes of preterm infants. Chorioamnionitis is often the first event and is the cause of 50% of preterm births < 28 weeks gestation [1,2,3,4,5] Many of these infants develop fetal inflammatory response syndrome (FIRS) [5], a severe, innate immune reaction to the mother’s infection that. It is likely that systemic inflammation is a key contributor to poor preterm infant outcomes that are associated with hippocampal development; the mechanism by which inflammation affects the hippocampus is not well understood
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