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Updated: Nov 14, 2025
A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
Fetal inflammation induces acute immune tolerance in the neonatal rat hippocampus
Garima Singh1, Bradley J Segura2, Michael K Georgieff1
1Division of Neonatology, Department of Pediatrics, University of Minnesota, East Building MB630, 2450 Riverside Avenue, Minneapolis, MN, 55454, USA.
Insights
Prenatal inflammation (FIRS) in preterm infants may reduce the brain's inflammatory response to later infections. This study found FIRS-induced immune tolerance in the hippocampus, impacting microglial activation and inflammatory mediator expression.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Preterm infants exposed to chorioamnionitis often develop fetal inflammatory response syndrome (FIRS) and face postnatal infections.
- Both FIRS and postnatal inflammation independently impair neurocognitive development in preterm infants.
- Hippocampal integrity is vital for neurocognition, and its functions are vulnerable to inflammation.
Purpose of the Study:
- To investigate how FIRS influences the hippocampal immune response to acute postnatal inflammatory events.
- To understand the mechanisms behind altered neuroinflammation in preterm infants.
Main Methods:
- Neonatal rats exposed prenatally to LPS (to model FIRS) or saline received postnatal LPS or saline.
- Hippocampal immune responses were assessed on postnatal day 7.
- Key markers included inflammatory gene expression, NFκB pathway proteins, microglial activation (CD11b+, Iba1+), and astrocyte reactivity (Gfap+).
Main Results:
- Postnatal LPS induced a strong hippocampal inflammatory response in control rats.
- Prenatal LPS exposure (FIRS) attenuated the response to postnatal LPS.
- This attenuation was seen as decreased inflammatory mediators, reduced nuclear NFκB p65, and fewer activated microglia, despite microglia showing inflammatory gene upregulation.
Conclusions:
- Prenatal LPS exposure establishes hippocampal immune tolerance to subsequent postnatal LPS.
- Microglia exhibit a robust inflammatory response to postnatal LPS but develop only partial immune tolerance following prenatal LPS exposure.
Background:
Infants 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.
Methods:
Prenatal 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.
Results:
Postnatal 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.
Conclusion:
Prenatal 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.
