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Systemic inflammation induces axon injury during brain inflammation

Systemic inflammation induces axon injury during brain inflammation
Systemic inflammation induces axon injury during brain inflammation
Objectives: axon injury is a key contributor to the progression of disability in multiple sclerosis (MS). Systemic infections, which frequently precede relapses in MS, have been linked to clinical progression in Alzheimer's disease. There is evidence of a role for the innate immune system in MS lesions as axonal injury is associated with macrophage activation. We hypothesize that systemic inflammation leads to enhanced axonal damage in MS as a consequence of innate immune system activation.

Methods: monophasic experimental allergic encephalomyelitis (EAE) was induced in a cohort of Lewis rats. The animals received a systemic challenge with either an inflammogen (LPS) or saline as a control, at 1, 3 or 6 weeks into the remission phase of the disease. The clinical outcome, cellular recruitment to lesions, degree of tissue damage and cytokine profiles were measured.

Results: we found that systemic inflammation activates the central nervous system (CNS) innate immune response and results in a switch in the macrophage/microglia phenotype. This switch was accompanied by iNOS and IL-1? expression and increased axon injury. This increased injury occurred independently of the re-emergence of overt clinical signs.

Interpretation: our evidence indicates that microglia/macrophages, associated with lesions, respond to circulating cytokines, produced in response to an inflammatory event outside the CNS, by producing immune mediators that lead to tissue damage. This has implications for people with MS, where prevention and stringent management of systemic infectious diseases may slow disease progression
0364-5134
932-942
Moreno, Beatriz
3cce0178-fad3-4a21-a1b9-43448c3c4079
Jukes, John-Paul
fa42adf1-5d25-402e-87b3-7a13a0b7a1b6
Vergara-Irigaray, Nuria
757a4fcf-885d-4dd1-929b-9a741396aff0
Errea, O.
1fef640a-142c-4dc3-ba0e-34ec84e94ba4
Villoslada, Pablo
336896d9-a0ed-4374-b5ad-fd8d29150666
Perry, V.H.
8f29d36a-8e1f-4082-8700-09483bbaeae4
Newman, T.A.
322290cb-2e9c-445d-a047-00b1bea39a25
Moreno, Beatriz
3cce0178-fad3-4a21-a1b9-43448c3c4079
Jukes, John-Paul
fa42adf1-5d25-402e-87b3-7a13a0b7a1b6
Vergara-Irigaray, Nuria
757a4fcf-885d-4dd1-929b-9a741396aff0
Errea, O.
1fef640a-142c-4dc3-ba0e-34ec84e94ba4
Villoslada, Pablo
336896d9-a0ed-4374-b5ad-fd8d29150666
Perry, V.H.
8f29d36a-8e1f-4082-8700-09483bbaeae4
Newman, T.A.
322290cb-2e9c-445d-a047-00b1bea39a25

Moreno, Beatriz, Jukes, John-Paul, Vergara-Irigaray, Nuria, Errea, O., Villoslada, Pablo, Perry, V.H. and Newman, T.A. (2011) Systemic inflammation induces axon injury during brain inflammation. Annals of Neurology, 70 (6), 932-942. (doi:10.1002/ana.22550). (PMID:22190366)

Record type: Article

Abstract

Objectives: axon injury is a key contributor to the progression of disability in multiple sclerosis (MS). Systemic infections, which frequently precede relapses in MS, have been linked to clinical progression in Alzheimer's disease. There is evidence of a role for the innate immune system in MS lesions as axonal injury is associated with macrophage activation. We hypothesize that systemic inflammation leads to enhanced axonal damage in MS as a consequence of innate immune system activation.

Methods: monophasic experimental allergic encephalomyelitis (EAE) was induced in a cohort of Lewis rats. The animals received a systemic challenge with either an inflammogen (LPS) or saline as a control, at 1, 3 or 6 weeks into the remission phase of the disease. The clinical outcome, cellular recruitment to lesions, degree of tissue damage and cytokine profiles were measured.

Results: we found that systemic inflammation activates the central nervous system (CNS) innate immune response and results in a switch in the macrophage/microglia phenotype. This switch was accompanied by iNOS and IL-1? expression and increased axon injury. This increased injury occurred independently of the re-emergence of overt clinical signs.

Interpretation: our evidence indicates that microglia/macrophages, associated with lesions, respond to circulating cytokines, produced in response to an inflammatory event outside the CNS, by producing immune mediators that lead to tissue damage. This has implications for people with MS, where prevention and stringent management of systemic infectious diseases may slow disease progression

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Published date: December 2011
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 194875
URI: http://eprints.soton.ac.uk/id/eprint/194875
ISSN: 0364-5134
PURE UUID: c444829a-b657-47de-a9c1-9605c7477fee
ORCID for T.A. Newman: ORCID iD orcid.org/0000-0002-3727-9258

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Date deposited: 12 Aug 2011 07:29
Last modified: 18 Feb 2021 16:46

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Contributors

Author: Beatriz Moreno
Author: John-Paul Jukes
Author: Nuria Vergara-Irigaray
Author: O. Errea
Author: Pablo Villoslada
Author: V.H. Perry
Author: T.A. Newman ORCID iD

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