CXC chemokine receptor-2 ligands are required for neutrophil-mediated hostdefense in experimental brain abscesses

We have developed a mouse brain abscess model by using Staphylococcus aureu s, one of the main etiologic agents of brain abscesses in humans. Direct da mage to the blood-brain barrier was observed from 24 h to 7 days after S. a ureus exposure as demonstrated by the accumulation of serum IgG in the brai n parenchyma. Evaluation of brain abscesses by immunohistochemistry and flo w cytometry revealed a prominent neutrophil infiltrate. To address the impo rtance of neutrophils in the early containment of S. aureus infection in th e brain, mice were transiently depleted of neutrophils before implantation of bacteria-laden beads. Neutrophil-depleted animals consistently demonstra ted more severe brain abscesses and higher CNS bacterial burdens compared w ith control animals. S. aureus led to the induction of numerous chemokines in the brain, including macrophage-inflammatory protein (MIP)-1 alpha /CCL3 , MIP-1 beta /CCL4, MIP-2/CXCL1, monocyte chemoattractant protein-1/CCL2, a nd TCA-3/ CCL1, within 6 h after bacterial exposure. These chemokines also were expressed by both primary cultures of neonatal mouse microglia and ast rocytes exposed to heat-inactivated S. aureus in vitro. Because neutrophils constitute the majority of the cellular infiltrate in early brain abscess development, subsequent analysis focused on MIP-2 and KC/CXCL1, two neutrop hil-attracting CXC chemokines. Both MIP-2 and KC protein levels were signif icantly elevated in the brain after S. aureus exposure. Neutrophil extravas ation into the brain parenchyma was impaired in CXCR2 knockout mice and was associated with increased bacterial burdens. These studies demonstrate the importance of the CXCR2 ligands MIP-2 and KC and neutrophils in the acute host response to S. aureus in the brain.