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 hav e demonstrated a ''window of susceptibility' in young animals during w hich the brain parenchyma is at greater risk of acute neutrophil-media ted breakdown of the blood-brain barrier [6,7]. The exact mechanism of this age-related susceptibility to brain inflammation has yet to be d efined, but animal models have revealed that the potent pro-inflammato ry cytokine interleukin-1 beta (IL-1 beta) 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 rapi d induction of CXC chemokines (which contain a Cys-X-Cys motif), in pa rticular the cytokine-induced neutrophil chemoattractant CINC-1, follo wing the intracerebral administration of IL-1 beta. The CXC chemokines produced a more intense neutrophil response in young rats than in adu lts. The IL-1 beta-induced blood-brain barrier breakdown in young rats could be attenuated by an anti-CINC-1 neutralising antibody. These re sults show that the immature central nervous system (CNS) is dramatica lly more susceptible to the chemotactic effects of CXC chemokines. Blo cking the CXC chemokine activity associated with brain inflammation in hibits neutrophil-mediated blood-brain barrier damage and represents a significant therapeutic possibility. (C) Current Biology Publications ISSN 0960-9822.