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Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration

Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration
Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration
The contribution of inflammation to the progression of eurodegenerative diseases such as Alzheimer’s, Parkinson’s, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are “primed” to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1 (IL-1) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in priondiseased mice than in control mice and induced microglial expression of IL-1. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.
0270-6474
9275-9284
Cunningham, Colm
3bc1d897-f0f5-4112-abf4-1a10c2e92a6b
Wilcockson, David C.
ba84a5a7-c06c-4d54-ba4d-1113c607e28e
Campion, Suzanne
3d67e320-84c4-4cd3-b278-09b0c8a4c040
Lunnon, Katie
c28c4d27-24b2-4f2a-8c25-f32b11fc29f7
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Cunningham, Colm
3bc1d897-f0f5-4112-abf4-1a10c2e92a6b
Wilcockson, David C.
ba84a5a7-c06c-4d54-ba4d-1113c607e28e
Campion, Suzanne
3d67e320-84c4-4cd3-b278-09b0c8a4c040
Lunnon, Katie
c28c4d27-24b2-4f2a-8c25-f32b11fc29f7
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4

Cunningham, Colm, Wilcockson, David C., Campion, Suzanne, Lunnon, Katie and Perry, V. Hugh (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. Journal of Neuroscience, 25 (40), 9275-9284. (doi:10.1523/JNEUROSCI.2614-05.2005).

Record type: Article

Abstract

The contribution of inflammation to the progression of eurodegenerative diseases such as Alzheimer’s, Parkinson’s, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are “primed” to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1 (IL-1) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in priondiseased mice than in control mice and induced microglial expression of IL-1. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.

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Published date: 5 October 2005

Identifiers

Local EPrints ID: 24018
URI: https://eprints.soton.ac.uk/id/eprint/24018
ISSN: 0270-6474
PURE UUID: 1092a503-51d1-490a-be03-dceb45cc1f35

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Date deposited: 17 Mar 2006
Last modified: 17 Jul 2017 16:15

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Contributors

Author: Colm Cunningham
Author: David C. Wilcockson
Author: Suzanne Campion
Author: Katie Lunnon
Author: V. Hugh Perry

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