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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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)
- PMC
- PMC3414763
- 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
- gold
- doi.org
- 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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