Cited by 104Neuroinflammation and Neurodegeneration MechanismsNeonatal and fetal brain pathologyNeonatal and Maternal Infections

Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects

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Cardoso, Filipa L, Herz, Jasmin, Fernandes, Adelaide, Rocha, João, Sepodes, Bruno, Brito, Maria A, McGavern, Dorian B, Brites, Dora·2015·Journal of Neuroinflammation

Abstract

BACKGROUND: The inflammatory mediator lipopolysaccharide (LPS) has been shown to induce acute gliosis in neonatal mice. However, the progressive effects on the murine neurodevelopmental program over the week that follows systemic inflammation are not known. Thus, we investigated the effects of repeated LPS administration in the first postnatal week in mice, a condition mimicking sepsis in late preterm infants, on the developing central nervous system (CNS). METHODS: Systemic inflammation was induced by daily intraperitoneal administration (i.p.) of LPS (6 mg/kg) in newborn mice from postnatal day (PND) 4 to PND6. The effects on neurodevelopment were examined by staining the white matter and neurons with Luxol Fast Blue and Cresyl Violet, respectively. The inflammatory response was assessed by quantifying the expression/activity of matrix metalloproteinases (MMP), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1, and autotaxin (ATX). In addition, B6 CX3CR1(gfp/+) mice combined with cryo-immunofluorescence were used to determine the acute, delayed, and lasting effects on myelination, microglia, and astrocytes. RESULTS: LPS administration led to acute body and brain weight loss as well as overt structural changes in the brain such as cerebellar hypoplasia, neuronal loss/shrinkage, and delayed myelination. The impaired myelination was associated with alterations in the proliferation and differentiation of NG2 progenitor cells early after LPS administration, rather than with excessive phagocytosis by CNS myeloid cells. In addition to disruptions in brain architecture, a robust inflammatory response to LPS was observed. Quantification of inflammatory biomarkers revealed decreased expression of ATX with concurrent increases in HMGB1, TLR-4, and MMP-9 expression levels. Acute astrogliosis (GFAP(+) cells) in the brain parenchyma and at the microvasculature interface together with parenchymal microgliosis (CX3CR1(+) cells) were also observed. These changes preceded the migration/proliferation of CX3CR1(+) cells around the vessels at later time points and the subsequent loss of GFAP(+) astrocytes. CONCLUSION: Collectively, our study has uncovered a complex innate inflammatory reaction and associated structural changes in the brains of neonatal mice challenged peripherally with LPS. These findings may explain some of the neurobehavioral abnormalities that develop following neonatal sepsis.

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Authors
Cardoso, F. L., Herz, J., Fernandes, A., Rocha, J., Sepodes, B., Brito, M. A., McGavern, D. B., & Brites, D.
Affiliations
  • University of Lisbon (PT)
  • National Institutes of Health (US)
Corresponding author
  • McGavern, Dorian B
  • Brites, Dora
Venue
Journal of Neuroinflammation
Published
2015-04-29
Volume
12
Issue
1
Pages
82-82
ISSN
1742-2094 (ISSN-L)
OpenAlex
W2031096177
Cited by
103
References
117
Citations by year
2026: 4 · 2025: 3 · 2024: 7 · 2023: 13 · 2022: 13 · 2021: 3 · 2020: 18 · 2019: 12 · 2018: 6 · 2017: 13 · 2016: 10 · 2015: 1
FWCI
5.33
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Universidade de Lisboa
  • Fundação Luso-Americana para o Desenvolvimento
  • National Institutes of Health
  • Fundação para a Ciência e a Tecnologia (COMPETE, PTDC/SAU-FAR/118787/2010, SFRH/BD/62959/2009, /2009)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Neonatal and Maternal Infections
Keywords
systemic inflammation, lipopolysaccharide, neonatal sepsis, brain development, myelination, cerebellar hypoplasia, neuroinflammation, astrocyte activation, microglial activation, autotaxin, HMGB1, TLR4, MMP-9, CX3CR1, astrocyte loss
MeSH terms
CX3C Chemokine Receptor 1, Age Factors, Anethole Trithione, Animals, Animals, Newborn, Body Weight, Cerebellum, Developmental Disabilities, Demyelinating Diseases, Myelin Basic Protein, Gene Expression Regulation, Inflammation, Lipopolysaccharides, Mice, Inbred C57BL, Mice, Transgenic, Nervous System Malformations, Time Factors, Microglia, Neurodegenerative Diseases, Receptors, Chemokine, HMGB1 Protein, Green Fluorescent Proteins, Toll-Like Receptor 4, Mice

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