However, TLR2-independent pathways have also been proposed to participate in S. Taken together, these studies indicate that in isolated leukocyte preparations, TLR2 is a dominant receptor for LTA and PGN, and has a significant role in the response to S. ( 12) found that dendritic cells from TLR2-deficient mice were unable to mature, or produce cytokines/chemokines in response to either PGN or LTA.
( 11) have also shown that thioglycolate-elicited macrophages from TLR2 −/− mice were unable to produce IL-6 or NO 2 −, and were severely impaired in terms of TNF production in response to PGN. aureus, compared with macrophages from wild-type mice. ( 10) demonstrated that TLR2-deficient peritoneal macrophages had significantly impaired production of both TNF and IL-6 in response to heat-killed S. TLR2 has been identified as the receptor responsible for immunorecognition of the Gram-positive bacteria Staphylococcus aureus as well as the Gram-positive bacterial components, lipoteichoic acid (LTA) and peptidoglycan (PGN) ( 10, 11, 12, 13, 14). 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-infected mice treated with a blocking Fab against C5aR. Morbidity was only significantly increased in S. Most importantly, bacterial clearance from the spleen and peritoneum was not altered in TLR2 −/− mice vs wild-type mice. aureus and found a similar degree of TLR2 involvement in leukocyte recruitment to that observed with PGN. By 24 h, the response to PGN involved primarily monocytes and was TLR2 and C5aR independent. Interestingly, macrophage-deficient mice did not have defective neutrophil recruitment. Peritoneal neutrophilia was partially mast cell dependent however, the defect could not be reconstituted with TLR2 −/− or C5aR −/− mast cells. Concomitant inhibition of TLR2 and C5aR resulted in a further reduction in PGN-induced peritonitis. PGN-mediated leukocyte recruitment was P-/E-selectin dependent but only partially TLR2 dependent, and also involved the C5aR.
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. We investigated whether the in vitro paradigm of TLR2 dominance would hold true in vivo. 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.
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