CD14 deficiency leads to increased MIP-2 production, CXCR2 expression, neutrophil transmigration, and early death in pneumococcal infection.
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.
Echchannaoui
Hakim
H
Department of Research, University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland.
Frei
Karl
K
Letiembre
Maryse
M
Strieter
Robert M
RM
Adachi
Yoshiyuki
Y
Landmann
Regine
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism / Q000473:pathology; D054426:Chemokine CXCL2; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000502:physiology*; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015846:Monokines / Q000096:biosynthesis* / Q000134:cerebrospinal fluid; D018375:Neutrophil Activation / Q000502:physiology; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000502:physiology*; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis*; D015996:Survival Rate
D000911:Antibodies, Monoclonal; D054426:Chemokine CXCL2; D018950:Lipopolysaccharide Receptors; D015846:Monokines; D023063:Receptors, Interleukin-8B