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S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis

Molecular Neurobiology volume 53, pages 3976–3991 (2016)Cite this article

Abstract

Multiple sclerosis (MS) pathology is characterized by neuroinflammation and demyelination. Recently, the inflammatory molecule S100B was identified in cerebrospinal fluid (CSF) and serum of MS patients. Although seen as an astrogliosis marker, lower/physiological levels of S100B are involved in oligodendrocyte differentiation/maturation. Nevertheless, increased S100B levels released upon injury may induce glial reactivity and oligodendrocyte demise, exacerbating tissue damage during an MS episode or delaying the following remyelination. Here, we aimed to unravel the functional role of S100B in the pathogenesis of MS. Elevated S100B levels were detected in the CSF of relapsing-remitting MS patients at diagnosis. Active demyelinating MS lesions showed increased expression of S100B and its receptor, the receptor for advanced glycation end products (RAGE), in the lesion area, while chronic active lesions displayed increased S100B in demyelinated areas with lower expression of RAGE in the rim. Interestingly, reactive astrocytes were identified as the predominant cellular source of S100B, whereas RAGE was expressed by activated microglia/macrophages. Using an ex vivo demyelinating model, cerebral organotypic slice cultures treated with lysophosphatidylcholine (LPC), we observed a marked elevation of S100B upon demyelination, which co-localized mostly with astrocytes. Inhibition of S100B action using a directed antibody reduced LPC-induced demyelination, prevented astrocyte reactivity and abrogated the expression of inflammatory and inflammasome-related molecules. Overall, high S100B expression in MS patient samples suggests its usefulness as a diagnostic biomarker for MS, while the beneficial outcome of its inhibition in our demyelinating model indicates S100B as an emerging therapeutic target in MS.

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Acknowledgments

This work was supported by Medal of Honor L’Oréal for Women in Science (FCT, UNESCO, L’Óreal) and innovation grant (Ordem dos Farmacêuticos) to AF, a post-doctoral grant from Fundação para a Ciência e Tecnologia (FCT-SFRH/BPD/96794/2013) and a DuPré Grant from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) to AB, and by FCT-Pest-OE/SAU/UI4013 to iMed.ULisboa.

Ethical Statement

The use of human samples was approved by the local institutional review board (IRB), both in Life and Health Sciences Research Institute (ICVS), Portugal, and VU University Medical Center Amsterdam, the Netherlands. Animal use complied with the Portuguese Law and the European Community Directive and followed the Federation of European Laboratory Animal Science Associations (FELASA) guidelines and recommendations concerning laboratorial animal welfare, being performed under the guidance of Adelaide Fernandes, with a FELASA level C certification (scientist), approved by the Portuguese Direção-Geral de Veterinária. This ensured that any suffering or other harmful effects experienced by the animals were minimized and have been weighted against the potential benefits to humans.

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  1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal

    Andreia Barateiro, Vera Afonso, Gisela Santos, Dora Brites & Adelaide Fernandes

  2. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal

    João José Cerqueira

  3. ICVS/3B’s—PT Government Associate Laboratory, Braga, Guimarães, Portugal

    João José Cerqueira

  4. Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal

    Dora Brites & Adelaide Fernandes

  5. Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands

    Jack van Horssen

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  1. Andreia Barateiro
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  2. Vera Afonso
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Correspondence to Adelaide Fernandes.

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Barateiro, A., Afonso, V., Santos, G. et al. S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis. Mol Neurobiol 53, 3976–3991 (2016). https://doi.org/10.1007/s12035-015-9336-6

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Keywords

  • Cerebellar organotypic slice cultures
  • Demyelination
  • Glial inflammatory response
  • Human samples
  • Multiple sclerosis
  • S100B