The role of TLR2 in vivo following challenge with Staphylococcus aureus and prototypic ligands.
Based on a wealth of in vitro macrophage studies, immunity to Staphylococcus aureus cell wall-derived peptidoglycan (PGN) and lipoteichoic acid has been attributed to TLR2. We investigated whether the in vitro paradigm of TLR2 dominance would hold true in vivo. Using an experimental peritonitis model, we challenged mice with PGN or lipoteichoic acid and found that only PGN resulted in significant leukocyte (primarily neutrophil) accumulation in the peritoneum at 4 h. PGN-mediated leukocyte recruitment was P-/E-selectin dependent but only partially TLR2 dependent, and also involved the C5aR. Concomitant inhibition of TLR2 and C5aR resulted in a further reduction in PGN-induced peritonitis. Peritoneal neutrophilia was partially mast cell dependent; however, the defect could not be reconstituted with TLR2(-/-) or C5aR(-/-) mast cells. Interestingly, macrophage-deficient mice did not have defective neutrophil recruitment. By 24 h, the response to PGN involved primarily monocytes and was TLR2 and C5aR independent. Finally, we challenged mice with live S. aureus and found a similar degree of TLR2 involvement in leukocyte recruitment to that observed with PGN. Most importantly, bacterial clearance from the spleen and peritoneum was not altered in TLR2(-/-) mice vs wild-type mice. Morbidity was only significantly increased in S. aureus-infected mice treated with a blocking Fab against C5aR. Taken together, these studies indicate that in vivo responses to prototypic TLR2 ligands do not necessarily recapitulate the absolute necessity for TLR2 observed in vitro, and additional receptors contribute, in a significant manner, to PGN and S. aureus-mediated immune responses.
Mullaly
Sarah C
SC
Immunology Research Group, Department of Physiology and Biophysics, Institute of Infection, Immunity, and Inflammation, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada.
Kubes
Paul
P
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D019007:P-Selectin / Q000276:immunology / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology*; D010538:Peritonitis / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology; D013682:Teichoic Acids / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology
D000942:Antigens, Bacterial; D019040:E-Selectin; D008024:Ligands; D008070:Lipopolysaccharides; D019007:P-Selectin; D010457:Peptidoglycan; D013682:Teichoic Acids; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C009900:lipoteichoic acid; D015936:Complement C5a