CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier breakdown.
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.
Anthony
D
D
Department of Pharmacology University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
Dempster
R
R
Fearn
S
S
Clements
J
J
Wells
G
G
Perry
V H
VH
Walker
K
K
D000328:Adult; D000375:Aging; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000276:immunology / Q000502:physiology / Q000503:physiopathology*; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000502:physiology*; D002630:Chemotactic Factors / Q000494:pharmacology / Q000502:physiology; D002648:Child; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology / Q000502:physiology; D006735:Horseradish Peroxidase / Q000493:pharmacokinetics; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D051379:Mice; D015846:Monokines / Q000494:pharmacology / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C513297:Cxcl1 protein, rat; C513296:Cxcl2 protein, rat; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D015846:Monokines; D011994:Recombinant Proteins; D006735:Horseradish Peroxidase