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Delays Central Nervous System Demyelination in the Presence of an Intact Blood-Brain Barrier1
,
,
,¶
*
Department of Microbiology and Immunology,
University of North Carolina-Neuroscience Center,
Department of Pathology and Laboratory Medicine,
Program of Molecular Biology and Biotechnology, and
¶ Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC 27599; and
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Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC 27710.
Chemokines are small chemotactic cytokines that modulate leukocyte
recruitment and activation during inflammation. Here, we describe the
role of macrophage inflammatory protein-1
(MIP-1) during
cuprizone intoxication, a model where demyelination of the CNS features
a large accumulation of microglia/macrophage without T cell involvement
or blood-brain barrier disruption. RNase protection assays showed that
mRNA for numerous chemokines were up-regulated during cuprizone
treatment in wild-type, C57BL/6 mice. RANTES, inflammatory protein-10,
and monocyte chemoattractant protein-1 showed greatest expression with
initiation of insult at 1–2 wk of treatment, whereas MIP-1 and 
increased later at 4–5 wk, coincident with peak demyelination and
cellular accumulation. The function of MIP-1 during demyelination
was tested in vivo by exposing MIP-1 knockout mice
(MIP-1-/-) to cuprizone and comparing pathology to
wild-type mice. Demyelination at 3.5 wk of treatment was significantly
decreased in MIP-1-/- mice (
36% reduction), a
result confirmed by morphology at the electron microscopic level. The
delay in demyelination was correlated to apparent decreases in
microglia/macrophage and astrocyte accumulation and in TNF- protein
levels. It was possible that larger effects of the MIP-1 deficiency
were being masked by other redundant chemokines. Indeed, RNase
protection assays revealed increased expression of several chemokine
transcripts in both untreated and cuprizone-treated
MIP-1-/- mice. Nonetheless, despite this possible
compensation, our studies show the importance of MIP-1 in
demyelination in the CNS and highlight its effect, particularly on
cellular recruitment and cytokine regulation.
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