Systemic inflammation induces axon injury during brain inflammation

Authors

  • Beatriz Moreno PhD,

    1. CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, UK
    2. Neuroimmunology Group, Institute of Biomedical Research August Pi Sunyer (IDIBAPS) Hospital Clinic, Barcelona, Spain
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  • John-Paul Jukes DPhil,

    1. CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, UK
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  • Nuria Vergara-Irigaray PhD,

    1. CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, UK
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  • Oihana Errea MSc,

    1. Neuroimmunology Group, Institute of Biomedical Research August Pi Sunyer (IDIBAPS) Hospital Clinic, Barcelona, Spain
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  • Pablo Villoslada MD, PhD,

    1. Neuroimmunology Group, Institute of Biomedical Research August Pi Sunyer (IDIBAPS) Hospital Clinic, Barcelona, Spain
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  • V. Hugh Perry DPhil,

    1. CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, UK
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  • Tracey A. Newman PhD

    Corresponding author
    1. CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, UK
    2. Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK
    • Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK SO17 BJ
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Abstract

Objective:

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 inflammagen (lipopolysaccharide [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 inducible nitric oxide synthase (iNOS) and interleukin-1β (IL-1β) 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, in which prevention and stringent management of systemic infectious diseases may slow disease progression. ANN NEUROL 2011;70:932–942

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