Search the site

The University of Manchester Library

In April 2016 Manchester eScholar was replaced by the University of Manchester’s new Research Information Management System, Pure. In the autumn the University’s research outputs will be available to search and browse via a new Research Portal. Until then the University’s full publication record can be accessed via a temporary portal and the old eScholar content is available to search and browse via this archive.

Related resources

Search for item elsewhere

University researcher(s)

    Academic department(s)

      Understanding mechanisms of NLRP3 inflammasome regulation

      Hoyle, Christopher

      [Thesis]. Manchester, UK: The University of Manchester; 2020.

      Access to files

      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.

      Bibliographic metadata

      Type of resource:
      Content type:
      Administered thesis
      Form of thesis:
      Alternative format
      Type of submission:
      Doctoral level ETD - final
      Thesis title:
      Understanding mechanisms of NLRP3 inflammasome regulation
      Degree type:
      Doctor of Philosophy
      Degree programme:
      PhD Neuroscience 3.5yr (NEP)
      Publication date:
      2020-06-12T10:46:48
      Institution:
      The University of Manchester
      Location:
      Manchester, UK
      Total pages:
      207
      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.
      Keyword(s):
      Thesis main supervisor(s):
      Thesis co-supervisor(s):
      Funder(s):
      Degree grantor:
      Language:
      en

      Institutional metadata

      University researcher(s):
      Academic department(s):

        Record metadata

        Manchester eScholar ID:
        uk-ac-man-scw:325074
        Created by:
        Hoyle, Christopher
        Created:
        12th June, 2020, 09:46:48
        Last modified by:
        Hoyle, Christopher
        Last modified:
        2nd July, 2020, 11:23:43

        Can we help?

        The library chat service will be available from 11am-3pm Monday to Friday (excluding Bank Holidays). You can also email your enquiry to us.