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Open Access 01-12-2016 | Research

Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques

Authors: Augusto F. Schmidt, Paranthaman S. Kannan, Claire A. Chougnet, Steve C. Danzer, Lisa A. Miller, Alan H. Jobe, Suhas G. Kallapur

Published in: Journal of Neuroinflammation | Issue 1/2016

Abstract

Background

Chorioamnionitis is associated with an increased risk of brain injury in preterm neonates. Inflammatory changes in brain could underlie this injury. Here, we evaluated whether neuroinflammation is induced by chorioamnionitis in a clinically relevant model.

Methods

Rhesus macaque fetuses were exposed to either intra-amniotic (IA) saline, or IA lipopolysaccharide (LPS) (1 mg) 16 or 48 h prior to delivery at 130 days (85 % of gestation) (n = 4–5 animals/group). We measured cytokines in the cerebrospinal fluid (CSF), froze samples from the left brain for molecular analysis, and immersion fixed the right brain hemisphere for immunohistology. We analyzed the messenger RNA (mRNA) levels of the pro-inflammatory cytokines IL-1β, CCL2, TNF-α, IL-6, IL-8, IL-10, and COX-2 in the periventricular white matter (PVWM), cortex, thalamus, hippocampus, and cerebellum by RT-qPCR. Brain injury was assessed by immunohistology for myelin basic protein (MBP), IBA1 (microglial marker), GFAP (astrocyte marker), OLIG2 (oligodendrocyte marker), NeuN (neuronal marker), CD3 (T cells), and CD14 (monocytes). Microglial proliferation was assessed by co-immunostaining for IBA1 and Ki67. Data were analyzed by ANOVA with Tukey’s post-test.

Results

IA LPS increased mRNA expression of pro-inflammatory cytokines in the PVWM, thalamus, and cerebellum, increased IL-6 concentration in the CSF, and increased apoptosis in the periventricular area after 16 h. Microglial proliferation in the white matter was increased 48 h after IA LPS.

Conclusions

LPS-induced chorioamnionitis caused neuroinflammation, microglial proliferation, and periventricular apoptosis in a clinically relevant model of chorioamnionitis in fetal rhesus macaques. These findings identify specific responses in the fetal brain and support the hypothesis that neuroinflammatory changes may mediate the adverse neurodevelopmental outcomes associated with chorioamnionitis.

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Title: Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques
Authors: Augusto F. Schmidt
Paranthaman S. Kannan
Claire A. Chougnet
Steve C. Danzer
Lisa A. Miller
Alan H. Jobe
Suhas G. Kallapur
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0706-4

At a glance: The STEP trials

Springer Medicine

Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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