Investigation of toll-like receptor tolerance in the regulation of inflammation

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dc.check.embargoformatNot applicableen
dc.check.infoNo embargo requireden
dc.check.opt-outNot applicableen
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dc.contributor.advisorMcCarthy, Tommie V.en
dc.contributor.advisorCarmody, Ruaidhrí J.en
dc.contributor.authorO'Carroll, Christine Elizabeth
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2014-02-10T16:23:56Z
dc.date.available2014-02-10T16:23:56Z
dc.date.issued2013
dc.date.submitted2014
dc.description.abstractInflammation is a complex and highly organised immune response to microbes and tissue injury. Recognition of noxious stimuli by pathogen recognition receptor families including Toll-like receptors results in the expression of hundreds of genes that encode cytokines, chemokines, antimicrobials and regulators of inflammation. Regulation of TLR activation responses is controlled by TLR tolerance which induces a global change in the cellular transcriptional expression profile resulting in gene specific suppression and induction of transcription. In this thesis the plasticity of TLR receptor tolerance is investigated using an in vivo, transcriptomics and functional approach to determine the plasticity of TLR tolerance in the regulation of inflammation. Firstly, using mice deficient in the negative regulator of TLR gene transcription, Bcl-3 (Bcl-3-/-) in a model of intestinal inflammation, we investigated the role of Bcl-3 in the regulation of intestinal inflammatory responses. Our data revealed a novel role for Bcl-3 in the regulation of epithelial cell proliferation and regeneration during intestinal inflammation. Furthermore this data revealed that increased Bcl-3 expression contributes to the development of inflammatory bowel disease (IBD). Secondly, we demonstrate that lipopolysaccharide tolerance is transient and recovery from LPS tolerance results in polarisation of macrophages to a previously un-described hybrid state (RM). In addition, we identified that RM cells have a unique transcriptional profile with suppression and induction of genes specific to this polarisation state. Furthermore, using a functional approach to characterise the outcomes of TLR tolerance plasticity, we demonstrate that cytokine transcription is uncoupled from cytokine secretion in macrophages following recovery from LPS tolerance. Here we demonstrate a novel mechanism of regulation of TLR tolerance through suppression of cytokine secretion in macrophages. We show that TNF-α is alternatively trafficked towards a degradative intracellular compartment. These studies demonstrate that TLR tolerance is a complex immunological response with the plasticity of this state playing an important role in the regulation of inflammation.en
dc.description.sponsorshipScience Foundation Ireland (CSET grant no. 07/CE/B1368)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationO'Carroll, C. E. 2013. Investigation of toll-like receptor tolerance in the regulation of inflammation. PhD Thesis, University College Cork.en
dc.identifier.endpage264
dc.identifier.urihttps://hdl.handle.net/10468/1379
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2013, Christine E. O'Carroll.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectToleranceen
dc.subjectInflammationen
dc.subjectMacrophageen
dc.subjectInflammationen
dc.subject.lcshInflammation--Immunological aspectsen
dc.subject.lcshMacrophages--Activationen
dc.thesis.opt-outfalse
dc.titleInvestigation of toll-like receptor tolerance in the regulation of inflammationen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Science)en
ucc.workflow.supervisort.mccarthy@ucc.ie
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