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

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dc.contributor.advisor McCarthy, Tommie V. en
dc.contributor.advisor Carmody, Ruaidhrí J. en
dc.contributor.author O'Carroll, Christine Elizabeth
dc.date.accessioned 2014-02-10T16:23:56Z
dc.date.available 2014-02-10T16:23:56Z
dc.date.issued 2013
dc.date.submitted 2014
dc.identifier.citation O'Carroll, C. E. 2013. Investigation of toll-like receptor tolerance in the regulation of inflammation. PhD Thesis, University College Cork. en
dc.identifier.endpage 264
dc.identifier.uri http://hdl.handle.net/10468/1379
dc.description.abstract Inflammation 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.sponsorship Science Foundation Ireland (CSET grant no. 07/CE/B1368) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Christine E. O'Carroll. en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Tolerance en
dc.subject Inflammation en
dc.subject Macrophage en
dc.subject Inflammation en
dc.subject.lcsh Inflammation--Immunological aspects en
dc.subject.lcsh Macrophages--Activation en
dc.title Investigation of toll-like receptor tolerance in the regulation of inflammation en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text available en
dc.check.info No embargo required en
dc.description.version Accepted Version
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en
dc.internal.school Alimentary Pharmabotic Centre en
dc.internal.school Biochemistry en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
ucc.workflow.supervisor t.mccarthy@ucc.ie
dc.internal.conferring Spring Conferring 2014 en


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© 2013, Christine E. O'Carroll. Except where otherwise noted, this item's license is described as © 2013, Christine E. O'Carroll.
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