Brain Advance Access originally published online on December 4, 2007
Brain 2008 131(1):288-303; doi:10.1093/brain/awm291
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection
1Neurobiology, Department of Research, University Hospital Basel, Pharmacenter, Basel, Switzerland and 2Department of Cellular & Molecular Neuroscience, Division of Neuroscience, Imperial College, Charing Cross Hospital Campus, London W6 8RP, UK
Correspondence to: Nicole Schaeren-Wiemers, Neurobiology, Department of Research, Pharmacenter 7007, Klingelberstrasse 50, CH-4056 Basel, Switzerland E-mail: nicole.schaeren-wiemers{at}unibas.ch
Multiple sclerosis is a chronic inflammatory disease of the CNS. Although progressive axonal injury and diffuse inflammatory damage has been shown in the chronic phase of the disease, little is known about the molecular mechanisms underlying these pathological processes. In order to identify these mechanisms, we have studied the gene expression profile in non-lesion containing tissue, the so-called normal-appearing white matter (NAWM). We performed differential gene expression analysis and quantitative RT-PCR on subcortical white matter from 11 multiple sclerosis and 8 control cases. Differentially expressed genes were further analysed in detail by in situ hybridization and immunofluorescence studies. We show that genes known to be involved in anti-inflammatory and protective mechanisms such as STAT6, JAK1, IL-4R, IL-10, Chromogranin C and Hif-1
are consistently upregulated in the multiple sclerosis NAWM. On the other hand, genes involved in pro-inflammatory mechanisms, such as STAT4, IL-1β and MCSF, were also upregulated but less regularly. Immunofluorescence colocalization analysis revealed expression of STAT6, JAK1, IL-4R and IL-13R mainly in oligodendrocytes, whereas STAT4 expression was detected predominantly in microglia. In line with these data, in situ hybridization analysis showed an increased expression in multiple sclerosis NAWM of HIF-1 in oligodendrocytes and HLA-DR in microglia cells. The consistency of the expression levels of STAT6, JAK1, JAK3 and IL-4R between the multiple sclerosis cases suggests an overall activation of the STAT6-signalling pathway in oligodendrocytes, whereas the expression of STAT4 and HLA-DR indicates the activation of pro-inflammatory pathways in microglia. The upregulation of genes involved in anti-inflammatory mechanisms driven by oligodendrocytes may protect the CNS environment and thus limit lesion formation, whereas the activation of pro-inflammatory mechanisms in microglia may favour disease progression. Altogether, our data suggests an endogenous inflammatory reaction throughout the whole white matter of multiple sclerosis brain, in which oligodendrocytes actively participate. This reaction might further influence and to some extent facilitate lesion formation.
Key Words: multiple sclerosis; inflammation; cytokines; chemokines; neuroprotection
Abbreviations: NAWM, normal-appearing white matter; EAE, experimental autoimmune encephalomyelitis; JAK, Janus tyrosine kinases; STAT, signal transducers and activators of transcription; MTI, magnetic transfer imaging
Received June 12, 2007. Revised October 31, 2007. Accepted November 1, 2007.