Understanding mechanisms of NLRP3 inflammasome regulation

UoM administered thesis: Phd

Abstract

The NLRP3 inflammasome is a multi-protein complex that contributes to immune responses during infection or injury. Upon activation, NLRP3 nucleates the formation of an ASC speck that drives caspase-1-dependent interleukin (IL)-1β and IL-18 processing and release, as well as pyroptotic cell death. NLRP3 is implicated in several diseases such as atherosclerosis, gout and Alzheimer’s disease, and therefore represents a promising therapeutic target. However, there are many facets of NLRP3 regulation that are incompletely characterised, and enhancing our mechanistic understanding of NLRP3 may facilitate the targeting of NLRP3 in disease. The aim of this thesis was to investigate multiple aspects of NLRP3 regulation. Firstly, this work describes an anti-inflammatory effect of graphene oxide (GO) treatment on macrophage NLRP3 responses. GO selectively limited lipopolysaccharide-induced expression of nuclear factor-κB-dependent gene subsets, including IL-1β, due to alterations in macrophage metabolism. Secondly, hallmarks of NLRP3 inflammasome activation were observed in organotypic hippocampal slice cultures, highlighting this as a valuable ex vivo brain model of microglial NLRP3 responses. Finally, the anti-inflammatory effects of itaconate treatment on macrophage immunometabolic regulation were further characterised, with itaconate limiting both priming and activation of NLRP3. Thus, the findings in this thesis inform future NLRP3 research by describing novel regulatory mechanisms of NLRP3 activation, as well as developing a model system in which we can interrogate NLRP3 responses in the context of the brain.

Details

Original languageEnglish
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Award date1 Aug 2020