Alternatively-spliced extra domain A of fibronectin promotes acute inflammation and brain injury after cerebral ischemia in mice.

Abstract

BACKGROUND AND PURPOSE:

The fibronectin isoform containing the alternatively spliced extra domain A (EDA(+)-FN) is normally absent from the circulation, but plasma levels of EDA(+)-FN can become markedly elevated in several human pathological conditions associated with inflammation including ischemic stroke. It remains unknown whether EDA(+)-FN contributes to stroke pathogenesis or is simply an associative marker. Several in vitro studies suggest that EDA(+)-FN can activate Toll-like receptor 4, an innate immune receptor that triggers proinflammatory responses. We undertook a genetic approach in mice to investigate the ability of EDA(+)-FN to mediate inflammatory brain damage in a focal cerebral ischemia/reperfusion injury model.

METHODS:

We used genetically modified EDA(+/+) mice, which constitutively express EDA(+)-FN. Extent of injury, neurological outcome, and inflammatory mechanisms were assessed after 1-hour cerebral ischemia/23-hour reperfusion injury and compared with wild-type mice.

RESULTS:

We found that EDA(+/+) mice developed significantly larger infarcts and severe neurological deficits that were associated with significant increased neutrophil and macrophage infiltration as quantitated by immunohistochemistry. Additionally, we found upregulation of nuclear factor-κB, cyclo-oxygenase-2, and inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the EDA(+/+) mice compared with wild-type mice. Interestingly, increased brain injury and neurological deficits were largely abrogated in EDA(+/+) mice by treatment with a specific Toll-like receptor 4 inhibitor.

CONCLUSIONS:

These findings provide the first evidence that EDA(+)-FN promotes inflammatory brain injury after ischemic stroke and suggest that the elevated levels of plasma EDA(+)-FN observed in chronic inflammatory conditions could worsen injury and outcome in patients after acute stroke.

• Authors: Mohammad Moshahid Khan, Chintan Gandhi, Neelam Chauhan, Jeff W Stevens, David G Motto, Steven R Lentz, Anil K Chauhan
• Journal: Stroke (Stroke) Vol. 43 Issue 5 Pg. 1376-82 (May 2012) ISSN: 1524-4628 [Electronic] United States
• PMID: 22363055 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Fibronectins
• NF-kappa B
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• extra domain A fibronectin, mouse
• Cyclooxygenase 2

Topics

• Alternative Splicing (genetics)
• Animals
• Brain Injuries (blood, etiology, physiopathology)
• Brain Ischemia (blood, complications, physiopathology)
• Cyclooxygenase 2 (physiology)
• Cytokines (physiology)
• Encephalitis (blood, etiology, physiopathology)
• Fibronectins (blood, genetics, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Animal
• NF-kappa B (physiology)
• Protein Structure, Tertiary (genetics)
• Time Factors
• Toll-Like Receptor 4 (physiology)
• Up-Regulation (physiology)