Innate inflammation's contribution to chronic neurodegeneration
Innate inflammation's contribution to chronic neurodegeneration
This thesis investigates the molecular mechanisms that underlie the changes in microglial molecular profile in chronic neurodegeneration during systemic inflammation. In prion disease, microglia appear morphologically similar to microglia seen in acute neuroinflammation and express an array of principally anti-inflammatory mediators including transforming growth factor-β (TGF- β) and prostaglandin E2 (PGE2); this phenotype has been described as ‘primed’. A systemic challenge with lipopolysaccharide (LPS) causes ‘primed’ microglia to switch to a pro-inflammatory phenotype and produce an array of pro-inflammatory mediators including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). This is accompanied by exaggerated sickness behaviours and neuronal apoptosis.
The molecular mechanisms that underlie microglial phenotype ‘switching’ in the ME7 model of prion disease are investigated in this thesis. The hippocampal transcriptome was compared in NBH control mice and ME7-infected mice, both with and without a systemic challenge of LPS. Genes encoding receptors that signal via an immunoreceptor tyrosine-based activation (ITAM) or immunoreceptor tyrosine-based inhibition motif (ITIM) were verified as being transcribed by qRT-PCR on hippocampal tissue punches and isolated microglia, and translated using immunocytochemistry. These experiments showed that ITAMs and ITIMs are up-regulated on ‘primed’ microglia in the ME7 model of prion disease. Following a systemic LPS challenge, the expression of ITAMs appears to increase relative to ITIMs. This is accompanied by the entry of immunoglobulin G (IgG), a ligand for the ITAM and ITIM utilising Fcγ receptors, into the parenchyma of the CNS. We hypothesis that LPS induces a switch in microglia in ME7-infected brain from a balanced ITAM/ITIM expression to an ITAM-dominated expression. In the presence of ligand, for example IgG, the ligand for Fcγ receptors, this may result in the exaggerated synthesis of pro-inflammatory mediators in ME7-infected brain.
University of Southampton
2007
Lunnon, Katie Sarah
(2007)
Innate inflammation's contribution to chronic neurodegeneration.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
This thesis investigates the molecular mechanisms that underlie the changes in microglial molecular profile in chronic neurodegeneration during systemic inflammation. In prion disease, microglia appear morphologically similar to microglia seen in acute neuroinflammation and express an array of principally anti-inflammatory mediators including transforming growth factor-β (TGF- β) and prostaglandin E2 (PGE2); this phenotype has been described as ‘primed’. A systemic challenge with lipopolysaccharide (LPS) causes ‘primed’ microglia to switch to a pro-inflammatory phenotype and produce an array of pro-inflammatory mediators including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). This is accompanied by exaggerated sickness behaviours and neuronal apoptosis.
The molecular mechanisms that underlie microglial phenotype ‘switching’ in the ME7 model of prion disease are investigated in this thesis. The hippocampal transcriptome was compared in NBH control mice and ME7-infected mice, both with and without a systemic challenge of LPS. Genes encoding receptors that signal via an immunoreceptor tyrosine-based activation (ITAM) or immunoreceptor tyrosine-based inhibition motif (ITIM) were verified as being transcribed by qRT-PCR on hippocampal tissue punches and isolated microglia, and translated using immunocytochemistry. These experiments showed that ITAMs and ITIMs are up-regulated on ‘primed’ microglia in the ME7 model of prion disease. Following a systemic LPS challenge, the expression of ITAMs appears to increase relative to ITIMs. This is accompanied by the entry of immunoglobulin G (IgG), a ligand for the ITAM and ITIM utilising Fcγ receptors, into the parenchyma of the CNS. We hypothesis that LPS induces a switch in microglia in ME7-infected brain from a balanced ITAM/ITIM expression to an ITAM-dominated expression. In the presence of ligand, for example IgG, the ligand for Fcγ receptors, this may result in the exaggerated synthesis of pro-inflammatory mediators in ME7-infected brain.
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Published date: 2007
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Local EPrints ID: 466374
URI: http://eprints.soton.ac.uk/id/eprint/466374
PURE UUID: 1433a44f-04ed-4586-98aa-472ecdc40e3e
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Date deposited: 05 Jul 2022 05:12
Last modified: 05 Jul 2022 05:12
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Author:
Katie Sarah Lunnon
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