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

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dc.contributor.authorButcher, Suzanne K.
dc.contributor.authorO'Carroll, Christine E.
dc.contributor.authorWells, Christine A.
dc.contributor.authorCarmody, Ruaidhrí J.
dc.contributor.funderMedical Research Council
dc.contributor.funderBiotechnology and Biological Sciences Research Council
dc.contributor.funderAustralian Research Council
dc.contributor.funderUniversity of Melbourne
dc.contributor.funderEuropean Cooperation in Science and Technology
dc.date.accessioned2018-05-31T11:56:28Z
dc.date.available2018-05-31T11:56:28Z
dc.description.abstractTolerance 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.sponsorshipMedical 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.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid933
dc.identifier.citationButcher, 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.2018.00933en
dc.identifier.doi10.3389/fimmu.2018.00933
dc.identifier.endpage11
dc.identifier.issn1664-3224
dc.identifier.issued2018
dc.identifier.journaltitleFrontiers in Immunologyen
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/6223
dc.identifier.volume9
dc.language.isoenen
dc.publisherFrontiers Mediaen
dc.relation.urihttps://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.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectToleranceen
dc.subjectMacrophageen
dc.subjectToll-like receptoren
dc.subjectTranscriptomeen
dc.subjectInnate immune memoryen
dc.subjectNF-κBen
dc.titleToll-like receptors drive specific patterns of tolerance and training on restimulation of macrophagesen
dc.typeArticle (peer-reviewed)en
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