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-aα, 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.
| Original language | English (US) |
|---|---|
| Article number | 238 |
| Journal | Journal of Neuroinflammation |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - Sep 6 2016 |
Fingerprint
Keywords
- Apoptosis
- Brain injury
- Chorioamnionitis
- Cytokines
- Microglia
- Periventricular leukomalacia
- Prematurity
ASJC Scopus subject areas
- Neuroscience(all)
- Immunology
- Neurology
- Cellular and Molecular Neuroscience
Cite this
Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques. / Schmidt, Augusto F.; Kannan, Paranthaman S.; Chougnet, Claire A.; Danzer, Steve C.; Miller, Lisa; Jobe, Alan H.; Kallapur, Suhas G.
In: Journal of Neuroinflammation, Vol. 13, No. 1, 238, 06.09.2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques
AU - Schmidt, Augusto F.
AU - Kannan, Paranthaman S.
AU - Chougnet, Claire A.
AU - Danzer, Steve C.
AU - Miller, Lisa
AU - Jobe, Alan H.
AU - Kallapur, Suhas G.
PY - 2016/9/6
Y1 - 2016/9/6
N2 - 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-aα, 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.
AB - 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-aα, 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.
KW - Apoptosis
KW - Brain injury
KW - Chorioamnionitis
KW - Cytokines
KW - Microglia
KW - Periventricular leukomalacia
KW - Prematurity
UR - http://www.scopus.com/inward/record.url?scp=84984994812&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84984994812&partnerID=8YFLogxK
U2 - 10.1186/s12974-016-0706-4
DO - 10.1186/s12974-016-0706-4
M3 - Article
C2 - 27596440
AN - SCOPUS:84984994812
VL - 13
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
SN - 1742-2094
IS - 1
M1 - 238
ER -