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Published online before print June 7, 2005
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* Division of Infectious Diseases, Department of Research, University Hospitals, Basel, Switzerland;
Department of Neurosurgery, University Hospital, Zurich, Switzerland;
Departments of Medicine and Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles; and
Laboratory of Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Science, Japan
1Correspondence: Division of Infectious Diseases, Department of Research, University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland. E-mail: Regine.Landmann{at}unibas.ch
CD14 is a myeloid receptor for bacterial cell membrane/wall components, for which we previously showed a strong induction in cerebrospinal fluid (CSF) during meningitis. Here, we studied CD14 function in murine Streptococcus pneumoniae meningitis by using wild-type (WT), CD14–/– mice, and WT mice pretreated with neutralizing anti-CD14 antibodies. Early polymorphonuclear leukocytes (PMN) immigration was more pronounced in CSF of CD14–/– than of WT mice. This was not a result of altered adherence molecule expression in blood and CSF PMN or brain endothelial cells. Macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine levels were similar in CSF in both strains, but MIP-2 was higher in infected brain and in brain-derived endothelial cells infected in vitro in CD14–/– than in WT mice. CD14–/– PMN demonstrated increased expression of CXC chemokine receptor 2 (CXCR2) after infection and stronger in vitro chemotaxis than WT PMN toward CSF from WT or CD14–/– mice and toward MIP-2. Excess PMN migration in CD14–/– mice did not result in improved bacterial clearing but in increased tumor necrosis factor in CSF, higher disease severity, and earlier death. Pretreatment with anti-CXCR2 reduced PMN infiltration into CSF and brain MIP-2 production and abolished earlier mortality in CD14–/– mice. In conclusion, CD14 plays a protective role in pneumococcal meningitis by slowing PMN migration via MIP-2 and CXCR2 modulation.
Key Words: chemokines • polymorphonuclear cells • meningitis
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