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The Role of TLR2 In Vivo following Challenge with Staphylococcus aureus and Prototypic Ligands¹

Immunology Research Group, Department of Physiology and Biophysics, Institute of Infection, Immunity, and Inflammation, University of Calgary, Calgary, Alberta, Canada

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Canadian Institutes of Health Research (CIHR) and a CIHR group grant. P.K. is a Canadian Research Chair recipient, the Joan Snyder Chair in Critical Care Medicine, and an Alberta Heritage Foundation for Medical Research Scientist. S.C.M. is funded by the Heart and Stroke Foundation of Canada and a Province of Alberta Graduate Scholarship.

² Address correspondence and reprint requests to Dr. Paul Kubes, Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. E-mail address: pkubes{at}ucalgary.ca

³ Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern; LTA, lipoteichoic acid; PGN, peptidoglycan; BMMC, bone marrow-derived mast cell; MPO, myeloperoxidase.

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