Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus

Ruth Gussenhoven,Luc J Zimmermann,Rob J J Westerlaken,Alan H Jobe,Pierre Gressens,Daan R M G Ophelders,Suhas G Kallapur,Stanislava Pankratova,Tim G A M Wolfs,Matthew W Kemp,Bobbi Fleiss,Per T Sangild,Boris W Kramer

doi:10.1186/s12974-018-1149-x

Abstract

BackgroundAntenatal infection (i.e., chorioamnionitis) is an important risk factor for adverse neurodevelopmental outcomes after preterm birth. Destructive and developmental disturbances of the white matter are hallmarks of preterm brain injury. Understanding the temporal effects of antenatal infection in relation to the onset of neurological injury is crucial for the development of neurotherapeutics for preterm infants. However, these dynamics remain unstudied.MethodsTime-mated ewes were intra-amniotically injected with lipopolysaccharide at 5, 12, or 24 h or 2, 4, 8, or 15 days before preterm delivery at 125 days gestational age (term ~ 150 days). Post mortem analyses for peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed. Moreover, considering the neuroprotective potential of erythropoietin (EPO) for perinatal brain injury, we evaluated (phosphorylated) EPO receptor (pEPOR) expression in the fetal brain following LPS exposure.ResultsIntra-amniotic exposure to this single bolus of LPS resulted in a biphasic systemic IL-6 and IL-8 response. In the developing brain, intra-amniotic LPS exposure induces a persistent microgliosis (IBA-1 immunoreactivity) but a shorter-lived increase in the pro-inflammatory marker COX-2. Cell death (caspase-3 immunoreactivity) was only observed when LPS exposure was greater than 8 days in the white matter, and there was a reduction in the number of (pre) oligodendrocytes (Olig2- and PDGFRα-positive cells) within the white matter at 15 days post LPS exposure only. pEPOR expression displayed a striking biphasic regulation following LPS exposure which may help explain contradicting results among clinical trials that tested EPO for the prevention of preterm brain injury.ConclusionWe provide increased understanding of the spatiotemporal pathophysiological changes in the preterm brain following intra-amniotic inflammation which may aid development of new interventions or implement interventions more effectively to prevent perinatal brain damage.

Highlights

IntroductionAntenatal infection (i.e., chorioamnionitis) is an important risk factor for adverse neurodevelopmental outcomes after preterm birth
Antenatal infection is an important risk factor for adverse neurodevelopmental outcomes after preterm birth
In a pre-clinical chorioamnionitis model, we showed that short-term (2 days) intra-amniotic exposure to lipopolysaccharide (LPS) resulted in systemic inflammation, overt microgliosis, and changes in myelin basic protein (MBP) immunoreactivity (IR) in the fetal ovine brain [8]

Summary

Introduction

Antenatal infection (i.e., chorioamnionitis) is an important risk factor for adverse neurodevelopmental outcomes after preterm birth. In a pre-clinical chorioamnionitis model, we showed that short-term (2 days) intra-amniotic exposure to lipopolysaccharide (LPS) resulted in systemic inflammation, overt microgliosis, and changes in myelin basic protein (MBP) immunoreactivity (IR) in the fetal ovine brain [8]. This systemic and cerebral phenotype was substantially different following longer exposure time (7 days) indicating that time-dependent peripheral and cerebral changes occur following intra-amniotic inflammation. Detailed studies elucidating the time-dependent effects of antenatal infection/inflammation in relation to neurological injury and development are crucial to gain insight in the pathophysiological changes in the fetal brain following antenatal stress Such temporal insight in the induction of brain injury following antenatal stress is essential to define the therapeutic window of opportunity for neurotherapeutics

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