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01-08-2014 | Original Paper

Demyelination during multiple sclerosis is associated with combined activation of microglia/macrophages by IFN-γ and alpha B-crystallin

Authors: Malika Bsibsi, Laura A. N. Peferoen, Inge R. Holtman, Peter J. Nacken, Wouter H. Gerritsen, Maarten E. Witte, Jack van Horssen, Bart J. L. Eggen, Paul van der Valk, Sandra Amor, Johannes M. van Noort

Published in: Acta Neuropathologica | Issue 2/2014

Abstract

Activated microglia and macrophages play a key role in driving demyelination during multiple sclerosis (MS), but the factors responsible for their activation remain poorly understood. Here, we present evidence for a dual-trigger role of IFN-γ and alpha B-crystallin (HSPB5) in this context. In MS-affected brain tissue, accumulation of the molecular chaperone HSPB5 by stressed oligodendrocytes is a frequent event. We have shown before that this triggers a TLR2-mediated protective response in surrounding microglia, the molecular signature of which is widespread in normal-appearing brain tissue during MS. Here, we show that IFN-γ, which can be released by infiltrated T cells, changes the protective response of microglia and macrophages to HSPB5 into a robust pro-inflammatory classical response. Exposure of cultured microglia and macrophages to IFN-γ abrogated subsequent IL-10 induction by HSPB5, and strongly promoted HSPB5-triggered release of TNF-α, IL-6, IL-12, IL-1β and reactive oxygen and nitrogen species. In addition, high levels of CXCL9, CXCL10, CXL11, several guanylate-binding proteins and the ubiquitin-like protein FAT10 were induced by combined activation with IFN-γ and HSPB5. As immunohistochemical markers for microglia and macrophages exposed to both IFN-γ and HSPB5, these latter factors were found to be selectively expressed in inflammatory infiltrates in areas of demyelination during MS. In contrast, they were absent from activated microglia in normal-appearing brain tissue. Together, our data suggest that inflammatory demyelination during MS is selectively associated with IFN-γ-induced re-programming of an otherwise protective response of microglia and macrophages to the endogenous TLR2 agonist HSPB5.

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Title: Demyelination during multiple sclerosis is associated with combined activation of microglia/macrophages by IFN-γ and alpha B-crystallin
Authors: Malika Bsibsi
Laura A. N. Peferoen
Inge R. Holtman
Peter J. Nacken
Wouter H. Gerritsen
Maarten E. Witte
Jack van Horssen
Bart J. L. Eggen
Paul van der Valk
Sandra Amor
Johannes M. van Noort
Publication date: 01-08-2014
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 2/2014
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-014-1317-8

Keynote webinar | Spotlight on medication adherence

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Demyelination during multiple sclerosis is associated with combined activation of microglia/macrophages by IFN-γ and alpha B-crystallin

Abstract

Keynote webinar | Spotlight on medication adherence

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Abstract

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