Role played by Toll-like receptors 2 and 4 in lipoteichoic acid-induced lung inflammation and coagulation.
BACKGROUND
The cell wall of Streptococcus pneumoniae consists of lipoteichoic acid (LTA), which is released when pneumococci are killed by either the host immune system or antibiotic treatment. Release of excessive amounts of LTA has been implicated in the toxic sequelae of severe gram-positive infection by virtue of its proinflammatory properties. Several in vitro studies have shown that LTA is recognized by Toll-like receptor (TLR) 2 and CD14. Our objective here was to investigate the inflammatory properties of S. pneumoniae LTA in vivo and the role played by TLR2, TLR4, and CD14 therein.


METHODS
Wild-type (WT), TLR2 knockout (KO), TLR4 KO, TLR2x4 double-KO, and CD14 KO mice were intranasally inoculated with highly purified pneumococcal LTA.


RESULTS
LTA induced a dose-dependent inflammatory response and activation of the coagulation and fibrinolytic pathways in a TLR2-dependent fashion. Surprisingly, TLR4 KO mice also displayed a somewhat diminished pulmonary inflammatory and coagulant response compared with WT mice, possibly as a result of absent TLR4 signaling through LTA-induced release of endogenous mediators.


CONCLUSIONS
Pneumococcal LTA induces a profound inflammatory response and activation of the coagulation pathway in the lungs in vivo through a TLR2-dependent route, which likely is amplified by endogenous TLR4 ligands.
Dessing
Mark C
MC
Center for Infection and Immunity Amsterdam, University of Amsterdam, Amsterdam, The Netherlands. m.c.dessing@amc.uva.nl
Schouten
Marcel
M
Draing
Christian
C
Levi
Marcel
M
von Aulock
Sonja
S
van der Poll
Tom
T
D000818:Animals; D001777:Blood Coagulation / Q000276:immunology* / Q000502:physiology; D005260:Female; D007249:Inflammation / Q000276:immunology* / Q000503:physiopathology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008168:Lung / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013047:Specific Pathogen-Free Organisms; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000472:pathogenicity*; D013682:Teichoic Acids / Q000276:immunology / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D013682:Teichoic Acids; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C009900:lipoteichoic acid