Inhibition of the BMP Signaling Pathway Ameliorated Established Clinical Symptoms of Experimental Autoimmune Encephalomyelitis

Neurotherapeutics volume 17, pages1988–2003(2020)Cite this article

Abstract

Bone morphogenetic proteins (BMPs) are secreted growth factors that belong to the transforming growth factor beta superfamily. BMPs have been implicated in physiological processes, but they are also involved in many pathological conditions. Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS); however, its etiology remains elusive. Some evidence points to BMPs as important players in the pathogenesis of inflammatory and autoimmune disorders. In the present work, we studied the expression of BMP2, BMP4, BMP5, BMP6, BMP7, BMP type II receptor, and noggin in the immune system during different phases of experimental autoimmune encephalomyelitis (EAE). Major changes in the expression of BMPs took place in the initial phases of EAE. Indeed, those changes mainly affected BMP6 (whose expression was abrogated), BMP2, and BMP7 (whose expression was increased). In addition, we showed that in vivo inhibition of the BMP signaling pathway with small molecules ameliorated the already established clinical symptoms of EAE, as well as the CNS histopathological features. At the immune level, we observed an expansion of plasmacytoid dendritic cells (pDCs) in mice treated with small molecules that inhibit the BMP signaling pathway. pDCs could play an important role in promoting the expansion of antigen-specific regulatory T cells. Altogether, our data suggest a role for BMPs in early immune events that take place in myelin oligodendrocyte glycoprotein (MOG)-induced EAE. In addition, the clinical outcome of the disease was improved when the BMP signaling pathway was inhibited in mice that presented established EAE symptoms.

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Acknowledgments

This work was supported by the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, and co-funded by the European Union (European Regional Development Fund/European Social Fund) “A way to build Europe” under grant PI12/02144.

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Affiliations

  1. Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya, Vall d’Hebron Institut de Recerca, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    Herena Eixarch, Laura Calvo-Barreiro, Carme Costa, Gemma Reverter-Vives, Mireia Castillo, Xavier Montalban & Carmen Espejo

  2. Universitat Autònoma de Barcelona, 08193, Bellaterra (Cerdanyola del Vallès), Spain

    Herena Eixarch, Laura Calvo-Barreiro, Carme Costa, Gemma Reverter-Vives, Mireia Castillo, Xavier Montalban & Carmen Espejo

  3. Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Parc Científic de Barcelona, Barcelona, Spain

    Vanessa Gil & José Antonio Del Río

  4. Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain

    Vanessa Gil & José Antonio Del Río

  5. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    Vanessa Gil & José Antonio Del Río

  6. Institute of Neuroscience, University of Barcelona, Barcelona, Spain

    Vanessa Gil & José Antonio Del Río

  7. Division of Neurology, St Michael’s Hospital, University of Toronto, Toronto, Canada

    Xavier Montalban

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  1. Herena Eixarch
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Eixarch, H., Calvo-Barreiro, L., Costa, C. et al. Inhibition of the BMP Signaling Pathway Ameliorated Established Clinical Symptoms of Experimental Autoimmune Encephalomyelitis. Neurotherapeutics 17, 1988–2003 (2020). https://doi.org/10.1007/s13311-020-00885-8

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Keywords

  • Multiple sclerosis
  • Experimental autoimmune encephalomyelitis
  • Bone morphogenetic protein
  • Immune response
  • Dorsomorphin
  • DMH1