Toll-like receptors drive specific patterns of tolerance and training on restimulation of macrophages

Butcher, S. K., O'Carroll, C. E., Wells, C. A. and Carmody, R. J. (2018) Toll-like receptors drive specific patterns of tolerance and training on restimulation of macrophages. Frontiers in Immunology, 9, 933. (doi: 10.3389/fimmu.2018.00933) (PMID:29867935) (PMCID:PMC5960718)

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Tolerance is a long-recognised property of macrophages that leads to an altered response to repeated or chronic exposure to endotoxin. The physiological role of tolerance is to limit the potential damage to host tissue that may otherwise result from prolonged production of pro-inflammatory cytokines. Tolerance is induced by all Toll-like receptor (TLR) ligands tested to date, however, tolerance induced by the TLR4 ligand lipopolysaccharide (LPS) is by far the best studied. LPS tolerance involves a global transcriptional shift from a pro-inflammatory response toward one characterised by the expression of anti-inflammatory and pro-resolution factors. Although largely reversible, LPS-tolerance leads to a hybrid macrophage activation state that is pro-inflammatory in nature but possesses distinct regulatory anti-inflammatory features. Remarkably, a comparative transcriptomic analysis of tolerance induced by different TLR ligands has not previously been reported. Here we describe the transcriptomic profiles of mouse macrophages tolerised with ligands for TLR2, TLR3, TLR4 and TLR 9. While we identified TLR-specific transcriptional profiles in macrophages tolerised with each ligand, tolerance induced by TLR4 represented an archetype pattern, such that each gene tolerised by any of the TLRs tested was also found to be tolerised by TLR4. Pro-inflammatory cytokines are not universally supressed in all tolerant cells but distinct patterns of cytokine expression distinguished TLR-specific tolerance. Analysis of gene regulatory regions revealed specific DNA sequence motifs associated with distinct states of TLR tolerance, implicating previously identified as well as novel transcriptional regulators of tolerance in macrophages. These data provide a basis for the future exploitation of TLR-specific tolerant states to achieve therapeutic re-programming of the innate immune response.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Carmody, Dr Ruaidhri
Authors: Butcher, S. K., O'Carroll, C. E., Wells, C. A., and Carmody, R. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Frontiers in Immunology
ISSN (Online):1664-3224
Copyright Holders:Copyright © 2018 Butcher, O’Carroll, Wells and Carmody
First Published:First published in Frontiers in Immunology 9:933
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
671081Investigating NF-kB p50 phosphorylation and the regulation of transcriptionRuaidhri CarmodyMedical Research Council (MRC)MR/M010694/1III -IMMUNOLOGY
659831Dissecting the function of Bcl-3 in NF-kappaB signaling in B cellsRuaidhri CarmodyBiotechnology and Biological Sciences Research Council (BBSRC)BB/M003671/1RI INFECTION IMMUNITY & INFLAMMATION