Absence of Macrophage-Inflammatory Protein-1α Delays Central Nervous System Demyelination in the Presence of an Intact Blood-Brain Barrier

Abstract

Chemokines are small chemotactic cytokines that modulate leukocyte recruitment and activation during inflammation. Here, we describe the role of macrophage inflammatory protein-1α (MIP-1α) 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-1α and β increased later at 4–5 wk, coincident with peak demyelination and cellular accumulation. The function of MIP-1α during demyelination was tested in vivo by exposing MIP-1α knockout mice (MIP-1α−/−) to cuprizone and comparing pathology to wild-type mice. Demyelination at 3.5 wk of treatment was significantly decreased in MIP-1α−/− 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-α protein levels. It was possible that larger effects of the MIP-1α 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-1α−/− mice. Nonetheless, despite this possible compensation, our studies show the importance of MIP-1α in demyelination in the CNS and highlight its effect, particularly on cellular recruitment and cytokine regulation.