TLR2 enhances NADPH oxidase activity and killing of Staphylococcus aureus by PMN.
Toll-like receptors play an essential role in the detection of invading pathogens. TLR2 is expressed in high concentrations on neutrophils and has been implicated as a critical mediator inducing host antimicrobial defenses against Gram-positive bacteria. Neutrophil responses induced via TLR2 are likely to have important clinical consequences, since Gram-positive organisms, such as Staphylococcus aureus, are an increasingly important source of severe infections. In the present study, we report that TLR2 has a central role in killing of S. aureus by murine PMN via enhancement of NADPH oxidase activity. PMN from TLR2-deficient mice showed a similar inability to kill S. aureus in vitro and under in vivo-like conditions as PMN with a non-functional NADPH oxidase. This defect in killing by TLR2-deficient PMN was not related to phagocytosis but caused by delayed and reduced NADPH oxidase-mediated production of superoxide anion in response to S. aureus and other Gram-positive bacteria. The cause of this was independent of PI3K- and p38 signaling. The TLR2-enhanced induction of superoxide was a defect in proper NADPH oxidase assembly. We hypothesize that early activation of TLR2-signaling may enhance p47(phox) phosphorylation subsequent to phagocytosis-mediated phosphorylation. Summarized, these data demonstrate a novel role of TLR2 in the killing of S. aureus by ensuring a rapid activation of the NADPH oxidase complex.
Jann
Naja J
NJ
Department of Biomedicine, Division of Infection Biology, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
Schmaler
Mathias
M
Ferracin
Fabrizia
F
Landmann
Regine
R
D000818:Animals; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*; D013481:Superoxides / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*
C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D013481:Superoxides; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1