Cited by 119Neonatal and fetal brain pathologyNeuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular Disturbances

JNK signaling is the shared pathway linking neuroinflammation, blood-brain barrier disruption and oligodendroglial apoptosis in the white matter injury of the immature brain

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Wang, Lan-Wan, Tu, Yi-Fang, Huang, Chao-Ching, Ho, Chien-Jung·2012·Journal of Neuroinflammation

Abstract

BACKGROUND: White matter injury is the major form of brain damage in very preterm infants. Selective white matter injury in the immature brain can be induced by lipopolysaccharide (LPS)-sensitized hypoxic-ischemia (HI) in the postpartum (P) day 2 rat pups whose brain maturation status is equivalent to that in preterm infants less than 30 weeks of gestation. Neuroinflammation, blood-brain barrier (BBB) damage and oligodendrocyte progenitor apoptosis may affect the susceptibility of LPS-sensitized HI in white matter injury. c-Jun N-terminal kinases (JNK) are important stress-responsive kinases in various forms of insults. We hypothesized that LPS-sensitized HI causes white matter injury through JNK activation-mediated neuroinflammation, BBB leakage and oligodendroglial apoptosis in the white matter of P2 rat pups. METHODS: P2 pups received LPS (0.05 mg/kg) or normal saline injection followed by 90-min HI. Immunohistochemistry and immunoblotting were used to determine microglia activation, TNF-α, BBB damage, cleaved caspase-3, JNK and phospho-JNK (p-JNK), myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) expression. Immunofluorescence was performed to determine the cellular distribution of p-JNK. Pharmacological and genetic approaches were used to inhibit JNK activity. RESULTS: P2 pups had selective white matter injury associated with upregulation of activated microglia, TNF-α, IgG extravasation and oligodendroglial progenitor apoptosis after LPS-sensitized HI. Immunohistochemical analyses showed early and sustained JNK activation in the white matter at 6 and 24 h post-insult. Immunofluorescence demonstrated upregulation of p-JNK in activated microglia, vascular endothelial cells and oligodendrocyte progenitors, and also showed perivascular aggregation of p-JNK-positive cells around the vessels 24 h post-insult. JNK inhibition by AS601245 or by antisense oligodeoxynucleotides (ODN) significantly reduced microglial activation, TNF-α immunoreactivity, IgG extravasation, and cleaved caspase-3 in the endothelial cells and oligodendrocyte progenitors, and also attenuated perivascular aggregation of p-JNK-positive cells 24 h post-insult. The AS601245 or JNK antisense ODN group had significantly increased MBP and decreased GFAP expression in the white matter on P11 than the vehicle or scrambled ODN group. CONCLUSIONS: LPS-sensitized HI causes white matter injury through JNK activation-mediated upregulation of neuroinflammation, BBB leakage and oligodendrocyte progenitor apoptosis in the immature brain.

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  • The neuroinflammatory state activates the JNK pathway in microglia and endothelial cells, leading to microglial and endothelial activation with direct and microglial-induced BBB disruption, further cytokine production and perpetuation of the neuroinflammatory process.

    “Recently, the neuroinflammatory state was shown to activate the c-Jun N-terminal kinase (JNK) pathway not only in microglia but also in ECs, leading to microglial and endothelial activation with direct and microglial-induced BBB disruption, further cytokine production and perpetuation of the neuroinflammatory process (Tu et al., 2011; Wang et al., 2012).”

    From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Wang et al., 2012

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Authors
Wang, L.-W., Tu, Y.-F., Huang, C.-C., & Ho, C.-J.
Affiliations
National Cheng Kung University (TW)
Corresponding author
Huang, Chao-Ching
Venue
Journal of Neuroinflammation
Published
2012-07-17
Volume
9
Issue
1
Pages
175-175
ISSN
1742-2094 (ISSN-L)
OpenAlex
W1971748792
Cited by
119
References
72
Citations by year
2026: 4 · 2025: 8 · 2024: 6 · 2023: 7 · 2022: 5 · 2021: 11 · 2020: 8 · 2019: 9 · 2018: 10 · 2017: 10 · 2016: 11 · 2015: 11 · 2014: 8 · 2013: 9 · 2012: 1
FWCI
8.15
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Science Council
  • National Health Research Institutes
  • Chi Mei Medical Center
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
JNK signaling, white matter injury, neuroinflammation, blood-brain barrier disruption, hypoxia-ischemia, preterm infants, microglial activation, TNF-α, IgG extravasation, JNK inhibition, oligodeoxynucleotides
MeSH terms
Animals, Animals, Newborn, Blood-Brain Barrier, Brain, Inflammation, Nerve Fibers, Myelinated, Oligodendroglia, Rats, Sprague-Dawley, Apoptosis, Hypoxia-Ischemia, Brain, MAP Kinase Signaling System, Rats

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