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Journal of Immunology Research
Volume 2016, Article ID 9345495, 13 pages
http://dx.doi.org/10.1155/2016/9345495
Research Article

Thrombin Cleavage of Osteopontin Modulates Its Activities in Human Cells In Vitro and Mouse Experimental Autoimmune Encephalomyelitis In Vivo

1Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), “A. Avogadro” University of Piemonte Orientale (UPO), 28100 Novara, Italy
2Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy
3Biocenter, Division for Experimental Pathophysiology and Immunology, Laboratory of Autoimmunity, Medical University of Innsbruck, 6020 Innsbruck, Austria
4Department of Translational Medicine, Neurology Unit, “A. Avogadro” UPO, 28100 Novara, Italy

Received 20 May 2016; Accepted 8 June 2016

Academic Editor: Yao Yao

Copyright © 2016 Elena Boggio et al. 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.

Abstract

Osteopontin is a proinflammatory cytokine and plays a pathogenetic role in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), by recruiting autoreactive T cells into the central nervous system. Osteopontin functions are modulated by thrombin cleavage generating N- and C-terminal fragment, whose individual roles are only partly known. Published data are difficult to compare since they have been obtained with heterogeneous approaches. Interestingly, thrombin cleavage of osteopontin unmasks a cryptic domain of interaction with α4β1 integrin that is the main adhesion molecule involved in lymphocyte transmigration to the brain and is the target for natalizumab, the most potent drug preventing relapses. We produced recombinant osteopontin and its N- and C-terminal fragments in an eukaryotic system in order to allow their posttranslational modifications. We investigated, in vitro, their effect on human cells and in vivo in EAE. We found that the osteopontin cleavage plays a key role in the function of this cytokine and that the two fragments exert distinct effects both in vitro and in vivo. These findings suggest that drugs targeting each fragment may be used to fine-tune the pathological effects of osteopontin in several diseases.