Fetal inflammation induces acute immune tolerance in the neonatal rat hippocampus

Abstract

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.

GM3 Ganglioside’s Efficacy in LPS-Induced Parkinsonism: Neuroprotection and Gliosis Mitigation

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ATAC and histone H3K9me3 landscapes revealed the altered epigenome by fetal-neonatal iron deficiency in the adult male rat hippocampus

“…Nevertheless, it is not surprising that the reduced accessibility occurred among loci regulating maturation of neurons and development of hippocampalcerebrocortical circuit, which may explain the impaired neurocognitive function exhibited by formerly ID animals (Kennedy et al, 2014(Kennedy et al, , 2018. Our group recently reported the effect of iron deficiency on neuroinflammation (Singh et al, 2021). Given the important role of microglia in neural development and function (Szepesi et al, 2018), the long-term decrease of neuroinflammation signaling pathways could contribute to the abnormal cognition and emotional behavior observed in the formerly ID adult rats (Carlson et al, 2007;Pisansky et al, 2013).…”

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“…While much of the literature to date focused on neurodegenerative stressors to prime microglia, there is emerging evidence that prenatal stressors can also induce innate immune memory. For example, Laiqi et al looked at microglia reactivity in newborn, adult, and aged primary microglia [ 109 , 149 , 150 ]. They found neonatal microglia had a greater susceptibility of LPS-induced priming and tolerance compared with adult and aged microglia [ 109 , 149 , 150 ].…”

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