Ej. Mcmahon et al., Absence of macrophage-inflammatory protein-1 alpha delays central nervous system demyelination in the presence of an intact blood-brain barrier, J IMMUNOL, 167(5), 2001, pp. 2964-2971
Chemokines are small chemotactic cytokines that modulate leukocyte recruitm
ent and activation during inflammation. Here, we describe the role of macro
phage inflammatory protein-1 alpha (MIP-1 alpha) during cuprizone intoxicat
ion, a model where demyelination of the CNS features a large accumulation o
f microglia/macrophage without T cell involvement or blood-brain barrier di
sruption. RNase protection assays showed that mRNA for numerous chemokines
were up-regulated during cuprizone treatment in wildtype, C57BL/6 mice. RAN
TES, inflammatory protein-10, and monocyte chemoattractant protein-1 showed
greatest expression with initiation of insult at 1-2 wk of treatment, wher
eas MIP-1 alpha and beta increased later at 4-5 wk, coincident with peak de
myelination and cellular accumulation. The function of MIP-1 alpha during d
emyelination was tested in vivo by exposing MIP-1 alpha knockout mice (MIP-
1 alpha (-/-)) to cuprizone and comparing pathology to wild-type mice. Demy
elination at 3.5 wk of treatment was significantly decreased in MIP-1 alpha
(-/-) mice (similar to 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 an
d in TNF-alpha protein levels. It was possible that larger effects of the M
IP-1 alpha deficiency were being masked by other redundant chemokines. Inde
ed, RNase protection assays revealed increased expression of several chemok
ine transcripts in both untreated and cuprizone-treated MIP-1 alpha (-/-) m
ice. Nonetheless, despite this possible compensation, our studies show the
importance of MIP-1 alpha in demyelination in the CNS and highlight its eff
ect, particularly on cellular recruitment and cytokine regulation.