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

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dc.contributor.author Butcher, Suzanne K.
dc.contributor.author O'Carroll, Christine E.
dc.contributor.author Wells, Christine A.
dc.contributor.author Carmody, Ruaidhrí J.
dc.date.accessioned 2018-05-31T11:56:28Z
dc.date.available 2018-05-31T11:56:28Z
dc.identifier.citation 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 (11pp). doi: 10.3389/fimmu.2018.00933 en
dc.identifier.volume 9
dc.identifier.issued 2018
dc.identifier.startpage 1
dc.identifier.endpage 11
dc.identifier.issn 1664-3224
dc.identifier.uri http://hdl.handle.net/10468/6223
dc.identifier.doi 10.3389/fimmu.2018.00933
dc.description.abstract Tolerance is a long-recognized 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 characterized 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 tolerized with ligands for TLR2, TLR3, TLR4 and TLR 9. While we identified TLR-specific transcriptional profiles in macrophages tolerized with each ligand, tolerance induced by TLR4 represented an archetype pattern, such that each gene tolerized by any of the TLRs tested was also found to be tolerized by TLR4. Pro-inflammatory cytokines are not universally suppressed 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. en
dc.description.sponsorship Medical Research Council (MR/M010694/1); Biotechnology and Biological Sciences Research Council (BB/M003671/1); European Cooperation in Science and Technology (COST Action BM1404 Mye-EUNITER); Australian Research Council (FT150100330; SR1101002); University of Melbourne (scholarship) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Frontiers Media en
dc.relation.uri https://www.frontiersin.org/articles/10.3389/fimmu.2018.00933/full
dc.rights © 2018, Butcher, O'Carroll, Wells and Carmody. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. en
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject Tolerance en
dc.subject Macrophage en
dc.subject Toll-like receptor en
dc.subject Transcriptome en
dc.subject Innate immune memory en
dc.subject NF-κB en
dc.title Toll-like receptors drive specific patterns of tolerance and training on restimulation of macrophages en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Christine O’Carroll, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. +353-21-490-3000 Email: christine.ocarroll@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder Medical Research Council
dc.contributor.funder Biotechnology and Biological Sciences Research Council
dc.contributor.funder Australian Research Council
dc.contributor.funder University of Melbourne
dc.contributor.funder European Cooperation in Science and Technology
dc.description.status Peer reviewed en
dc.identifier.journaltitle Frontiers in Immunology en
dc.internal.IRISemailaddress christine.ocarroll@ucc.ie en
dc.identifier.articleid 933


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© 2018, Butcher, O'Carroll, Wells and Carmody. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Except where otherwise noted, this item's license is described as © 2018, Butcher, O'Carroll, Wells and Carmody. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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