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Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice

D. Sorcini, S. Bruscoli, T. Frammartino, M. Cimino, E. Mazzon, M. Galuppo, P. Bramanti, M. Al-Banchaabouchi, D. Farley, O. Ermakova, O. Britanova, M. Izraelson, D. Chudakov, M. Biagioli, P. Sportoletti, S. Flamini, M. Raspa, F. Scavizzi, C....

. 2017 ; 199 (9) : 3031-3041. [pub] 20170922

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc18016329

The mechanisms leading to autoimmune and inflammatory diseases in the CNS have not been elucidated. The environmental triggers of the aberrant presence of CD4+ T cells in the CNS are not known. In this article, we report that abnormal β-catenin expression in T cells drives a fatal neuroinflammatory disease in mice that is characterized by CNS infiltration of T cells, glial activation, and progressive loss of motor function. We show that enhanced β-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin α4β1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of β-catenin in mature naive T cells was sufficient to drive integrin α4β1 expression and CNS migration, whereas pharmacologic inhibition of integrin α4β1 reduced the abnormal T cell presence in the CNS of β-catenin-expressing mice. Together, these results implicate deregulation of the Wnt/β-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders.

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$a The mechanisms leading to autoimmune and inflammatory diseases in the CNS have not been elucidated. The environmental triggers of the aberrant presence of CD4+ T cells in the CNS are not known. In this article, we report that abnormal β-catenin expression in T cells drives a fatal neuroinflammatory disease in mice that is characterized by CNS infiltration of T cells, glial activation, and progressive loss of motor function. We show that enhanced β-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin α4β1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of β-catenin in mature naive T cells was sufficient to drive integrin α4β1 expression and CNS migration, whereas pharmacologic inhibition of integrin α4β1 reduced the abnormal T cell presence in the CNS of β-catenin-expressing mice. Together, these results implicate deregulation of the Wnt/β-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders.
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$a Mazzon, Emanuela $u Istituto di Ricovero e Cura a Carattere Scientifico, Centro Neurolesi "Bonino Pulejo," Messina 98124, Italy.
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$a Ermakova, Olga $u Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo 00015, Italy. Consiglio Nazionale delle Ricerche, Istituto di Biologia Cellulare e Neurobiologia, Monterotondo 00015, Italy.
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$a Britanova, Olga $u Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, 117997 Moscow, Russia. Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic; and. Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
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$a Izraelson, Mark $u Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, 117997 Moscow, Russia. Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic; and. Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
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$a Chudakov, Dmitry $u Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, 117997 Moscow, Russia. Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic; and. Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
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$a Biagioli, Michele $u Department of Medicine, University of Perugia, Perugia 06132, Italy.
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$a Sportoletti, Paolo $u Department of Medicine, University of Perugia, Perugia 06132, Italy.
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$a Flamini, Sara $u Department of Medicine, University of Perugia, Perugia 06132, Italy.
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$a Raspa, Marcello $u Consiglio Nazionale delle Ricerche, Istituto di Biologia Cellulare e Neurobiologia, Monterotondo 00015, Italy.
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$a Nerlov, Claus $u Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo 00015, Italy.
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$a Riccardi, Carlo $u Department of Medicine, University of Perugia, Perugia 06132, Italy.
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$a Bereshchenko, Oxana $u Department of Medicine, University of Perugia, Perugia 06132, Italy; oxana.bereshchenko@unipg.it. Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo 00015, Italy.
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