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Untangling Extracellular Proteasome-Osteopontin Circuit Dynamics in Multiple Sclerosis

Department of Drug Science and Technology, University of Turin, 10126 Torino, Italy
Interdisciplinary Research Centre of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Amedeo Avogadro, 28100 Novara, Italy
Department of Biomedical Sciences for Health, University of Milan, 20122 Milan, Italy
MS Research Unit and Department of Neurology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy
Department of Biomedical, Surgical and Dental Sciences, University of Milan, “Dino Ferrari” Centre, 20100 Milano, Italy
Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, 20100 Milano, Italy
Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale, 28100 Novara, Italy
Centre for Inflammation Biology and Cancer Immunology (CIBCI) & Peter Gorer Department of Immunobiology, King’s College London, SE1 1UL London, UK
Institute for Biochemistry, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Biochemie, Germany, 10117 Berlin, Germany
Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany
Authors to whom correspondence should be addressed.
These authors equally contributed.
Cells 2019, 8(3), 262;
Received: 14 January 2019 / Revised: 14 March 2019 / Accepted: 18 March 2019 / Published: 20 March 2019
(This article belongs to the Special Issue Adding New Pieces in the Osteopontin Puzzle)
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The function of proteasomes in extracellular space is still largely unknown. The extracellular proteasome-osteopontin circuit has recently been hypothesized to be part of the inflammatory machinery regulating relapse/remission phase alternation in multiple sclerosis. However, it is still unclear what dynamics there are between the different elements of the circuit, what the role of proteasome isoforms is, and whether these inflammatory circuit dynamics are associated with the clinical severity of multiple sclerosis. To shed light on these aspects of this novel inflammatory circuit, we integrated in vitro proteasome isoform data, cell chemotaxis cell culture data, and clinical data of multiple sclerosis cohorts in a coherent computational inference framework. Thereby, we modeled extracellular osteopontin-proteasome circuit dynamics during relapse/remission alternation in multiple sclerosis. Applying this computational framework to a longitudinal study on single multiple sclerosis patients suggests a complex interaction between extracellular proteasome isoforms and osteopontin with potential clinical implications. View Full-Text
Keywords: immunoproteasome; chemotaxis; computational modelling; system biology immunoproteasome; chemotaxis; computational modelling; system biology

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Dianzani, C.; Vecchio, D.; Clemente, N.; Chiocchetti, A.; Martinelli Boneschi, F.; Galimberti, D.; Dianzani, U.; Comi, C.; Mishto, M.; Liepe, J. Untangling Extracellular Proteasome-Osteopontin Circuit Dynamics in Multiple Sclerosis. Cells 2019, 8, 262.

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