TLR9-independent effects of inhibitory oligonucleotides on macrophage responses to S. typhimurium

Trieu, A., Bokil, N., Dunn, J. A., Roberts, T. L., Xu, D., Liew, F. Y., Hume, D. A., Stacey, K. J. and Sweet, M. J. (2009) TLR9-independent effects of inhibitory oligonucleotides on macrophage responses to S. typhimurium. Immunology and Cell Biology, 87(3), pp. 218-225. (doi: 10.1038/icb.2008.95)

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Publisher's URL: http://dx.doi.org/10.1038/icb.2008.95

Abstract

Detection of bacterial CpG-containing DNA (CpG DNA) by innate immune cells is dependent on toll-like receptor 9 (TLR9). Here we show that the expression of tlr9 mRNA was induced in mouse bone marrow-derived macrophages (BMMs) upon infection with the facultative Gram-negative intracellular bacterium Salmonella enteric serovar Typhimurium (S. typhimurium). Treatment of BMM with the inhibitory oligonucleotide (ODN) 2114, an antagonist of TLR9 signalling, enhanced intracellular S. Typhimurium numbers approximately fivefold, whereas a control ODN (2310) had no significant effect. Surprisingly, 2114 also amplified S. Typhimurium bacterial loads in TLR9-deficient BMM. Indeed, 2114 suppressed responses (nuclear factor-κB-dependent reporter gene expression and interleukin-12p40 secretion) to not only CpG DNA, but also the TLR2 ligand Pam3Cys, in BMM and RAW264 cells in a sequence-specific manner. Inhibitory ODNs, which have been proposed as therapeutic agents for the treatment of systemic lupus erythematosus because of their inhibitory effects on TLR9 signalling, may thus compromise the host response to bacterial pathogens through TLR9-independent mechanisms.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liew, Prof Foo and Xu, Dr Damo
Authors: Trieu, A., Bokil, N., Dunn, J. A., Roberts, T. L., Xu, D., Liew, F. Y., Hume, D. A., Stacey, K. J., and Sweet, M. J.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Immunology and Cell Biology
Publisher:Nature Publishing Group
ISSN:0818-9641
ISSN (Online):1440-1711
Published Online:02 December 2008
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
380241Toll-like receptors on T cellsFoo LiewMedical Research Council (MRC)G9818261Infection Immunity and Inflammation Medicine
486461The role of IL-35 in infection and inflammationFoo LiewMedical Research Council (MRC)G0801198III -IMMUNOLOGY