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CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier
D Anthony1, R Dempster, S Fearn
1Department of Pharmacology University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
Insights
Young brains are more vulnerable to inflammation and damage after injury due to a heightened response to specific inflammatory signals called CXC chemokines. Blocking these signals may protect developing brains.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Children face higher risks of brain damage and mortality from head injuries or infections compared to adults.
- Rodent models reveal a 'window of susceptibility' in young animals, where the brain is more prone to neutrophil-mediated blood-brain barrier damage.
- Interleukin-1beta (IL-1beta) triggers a robust neutrophil-mediated inflammatory response in young rodents, unlike in adults.
Purpose of the Study:
- To investigate the mechanisms behind age-related susceptibility to brain inflammation.
- To identify specific inflammatory mediators responsible for increased brain damage in young animals.
- To explore potential therapeutic targets for mitigating brain injury in immature central nervous systems.
Main Methods:
- Intracerebral administration of interleukin-1beta (IL-1beta) in young and adult rodent models.
- Measurement of CXC chemokine induction, particularly cytokine-induced neutrophil chemoattractant (CINC-1).
- Assessment of neutrophil response and blood-brain barrier integrity.
- Administration of an anti-CINC-1 neutralising antibody to evaluate its protective effects.
Main Results:
- Interleukin-1beta (IL-1beta) rapidly induced CXC chemokines, including CINC-1, in the brains of young rats.
- Young rats exhibited a more intense neutrophil response to IL-1beta compared to adult rats.
- An anti-CINC-1 neutralising antibody significantly attenuated IL-1beta-induced blood-brain barrier breakdown in young rats.
Conclusions:
- The immature central nervous system (CNS) is highly susceptible to the chemotactic effects of CXC chemokines.
- CXC chemokines, such as CINC-1, play a critical role in mediating neutrophil-induced blood-brain barrier damage in young brains.
- Blocking CXC chemokine activity presents a promising therapeutic strategy for preventing brain inflammation and damage in vulnerable pediatric populations.
Abstract:
Children are at greater risk than adults of permanent brain damage and mortality following head injury or infection [1-5]. Rodent models have demonstrated a 'window of susceptibility' in young animals during which the brain parenchyma is at greater risk of acute neutrophil-mediated breakdown of the blood-brain barrier [6-7]. The exact mechanism of this age-related susceptibility to brain inflammation has yet to be defined, but animal models have revealed that the potent pro-inflammatory cytokine interleukin-1beta (IL-1beta) initiates an intense acute neutrophil-mediated inflammatory response in the brains of young rats and mice that is not seen in adults [6]. Here, we demonstrate the rapid induction of CXC chemokines (which contain a Cys-X-Cys motif), in particular the cytokine-induced neutrophil chemoattractant CINC-1, following the intracerebral administration of IL-1beta. The CXC chemokines produced a more intense neutrophil response in young rats than in adults. The IL-1beta-induced blood-brain barrier breakdown in young rats could be attenuated by an anti-CINC-1 neutralising antibody. These results show that the immature central nervous system (CNS) is dramatically more susceptible to the chemotactic effects of CXC chemokines. Blocking the CXC chemokine activity associated with brain inflammation inhibits neutrophil-mediated blood-brain barrier damage and represents a significant therapeutic possibility.