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

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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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Acknowledgments

We are grateful to the microarray core facility of the VU University Medical Centre, Amsterdam for their assistance in performing the microarray experiments. This study was sponsored by Delta Crystallon BV. We also acknowledge support from the Stichting MS research (Dutch MS society) for Dr. Peferoen (grant MS 10-726).

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Authors and Affiliations

  1. Delta Crystallon, Zernikedreef 9, 2333, CK Leiden, The Netherlands

    Malika Bsibsi, Peter J. Nacken & Johannes M. van Noort

  2. Department of Pathology, VU University Medical Center, 1081, HV Amsterdam, The Netherlands

    Laura A. N. Peferoen, Wouter H. Gerritsen, Paul van der Valk & Sandra Amor

  3. Department of Medical Physiology, University Medical Centre Groningen, 9713, AV Groningen, The Netherlands

    Inge R. Holtman & Bart J. L. Eggen

  4. Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081, HV Amsterdam, The Netherlands

    Maarten E. Witte & Jack van Horssen

  5. Department of Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, London, UK

    Sandra Amor

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  1. Malika Bsibsi
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Bsibsi, M., Peferoen, L.A.N., Holtman, I.R. et al. Demyelination during multiple sclerosis is associated with combined activation of microglia/macrophages by IFN-γ and alpha B-crystallin. Acta Neuropathol 128, 215–229 (2014). https://doi.org/10.1007/s00401-014-1317-8

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