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Wnt/Β-Catenin Signaling Induces Integrin Α4β1 in T Cells And

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Wnt/Β-Catenin Signaling Induces Integrin Α4β1 in T Cells And Wnt/β-Catenin Signaling Induces Integrin α4 β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice This information is current as Daniele Sorcini, Stefano Bruscoli, Tiziana Frammartino, of September 27, 2021. Monica Cimino, Emanuela Mazzon, Maria Galuppo, Placido Bramanti, Mumna Al-Banchaabouchi, Dominika Farley, Olga Ermakova, Olga Britanova, Mark Izraelson, Dmitry Chudakov, Michele Biagioli, Paolo Sportoletti, Sara Flamini, Marcello Raspa, Ferdinando Scavizzi, Claus Nerlov, Graziella Migliorati, Carlo Riccardi and Oxana Downloaded from Bereshchenko J Immunol 2017; 199:3031-3041; Prepublished online 22 September 2017; doi: 10.4049/jimmunol.1700247 http://www.jimmunol.org/content/199/9/3031 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2017/09/22/jimmunol.170024 Material 7.DCSupplemental References This article cites 51 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/199/9/3031.full#ref-list-1 by guest on September 27, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Wnt/b-Catenin Signaling Induces Integrin a4b1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice Daniele Sorcini,*,1 Stefano Bruscoli,*,1 Tiziana Frammartino,* Monica Cimino,* Emanuela Mazzon,† Maria Galuppo,† Placido Bramanti,† Mumna Al-Banchaabouchi,‡ Dominika Farley,‡ Olga Ermakova,‡,x Olga Britanova,{,‖,# Mark Izraelson,{,‖,# Dmitry Chudakov,{,‖,# Michele Biagioli,* Paolo Sportoletti,* Sara Flamini,* Marcello Raspa,x Ferdinando Scavizzi,x Claus Nerlov,‡ Graziella Migliorati,* Carlo Riccardi,*,1 and Oxana Bereshchenko*,‡,1 Downloaded from 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 b-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 b-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin a4b1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of b-catenin in mature naive T cells was sufficient to drive http://www.jimmunol.org/ integrin a4b1 expression and CNS migration, whereas pharmacologic inhibition of integrin a4b1 reduced the abnormal T cell presence in the CNS of b-catenin–expressing mice. Together, these results implicate deregulation of the Wnt/b-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders. The Journal of Immunology, 2017, 199: 3031–3041. n increased presence of activated T cells in organs is T (Treg) cell subsets define the duration of immune responses and associated with the development of autoimmune and the outcome of many autoimmune and inflammatory diseases (1, inflammatory diseases (1–4). Balanced activation and 3, 5). Although there is strong evidence for the involvement of A by guest on September 27, 2021 differentiation of T lymphocytes into specific Th and regulatory CD4+ T cells in the pathogenesis of several neuroinflammatory diseases, their causative role in disease initiation has not been demonstrated. The environmental triggers and molecular deter- *Department of Medicine, University of Perugia, Perugia 06132, Italy; minants of T cell–mediated diseases of the CNS have not been † Istituto di Ricovero e Cura a Carattere Scientifico, Centro Neurolesi “Bonino fully characterized and require further exploration. Pulejo,” Messina 98124, Italy; ‡Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo 00015, Italy; xConsiglio Nazionale delle Ricerche, Istituto The deregulation of the Wnt/b-catenin pathway was recently di Biologia Cellulare e Neurobiologia, Monterotondo 00015, Italy; {Shemyakin- detected in several neurodegenerative diseases, including Alz- Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, 117997 Moscow, Russia; ‖Central European Institute of Technology, Masaryk Uni- heimer’s disease (6), Parkinson’s disease (7), and multiple scle- versity, Brno 625 00, Czech Republic; and #Pirogov Russian National Research rosis (8–10). Elevated expression of Wnt3a and b-catenin was Medical University, 117997 Moscow, Russia detected in spinal cords during experimental autoimmune en- 1D.S., S.B., C.R., and O. Bereshchenko contributed equally to this work. cephalomyelitis (EAE) (11). Activation of the Wnt signaling ORCIDs: 0000-0002-5073-717X (E.M.); 0000-0001-9173-324X (D.F.); 0000-0001-8365- pathway was detected in T cells in relapsing uveitis in rats (12), 4904 (O.E.); 0000-0003-0430-790X (D.C.); 0000-0002-2995-6896 (M.B.); 0000-0002- 5630-9862 (P.S.); 0000-0002-6994-8428 (S.F.); 0000-0002-3437-2430 (M.R.); 0000- and it underlies the pathogenesis of neuropathic pain in rodents 0001-9257-3997 (C.R.); 0000-0002-2772-6042 (O. Bereshchenko). (13). The expression of Wnt signaling components in immune-like Received for publication February 21, 2017. Accepted for publication August 22, cells of the CNS, including macrophages/microglia and astrocytes, 2017. as well as in oligodendrocytes, suggests that they contribute to This work was partly supported by the Italian Ministry of Education and Research inflammation-driven brain repair or damage (14, 15). However, (Progetti di Ricerca di Rilevante Interesse Nazionale, Bando 2015 2015ZT9HXY to C.R. and 20153NBRS3 to S.B., and Programma Futuro in Ricerca 2013 RBFR13BN6Y whether specific activation of the Wnt/b-catenin pathway in to O. Bereshchenko) and by Russian Science Foundation Project 16-15-00149. T cells triggers the pathogenesis of autoimmune and inflammatory Address correspondence and reprint requests to Dr. Oxana Bereshchenko, University diseases in the CNS has not been investigated. of Perugia, Department of Medicine, Section of Pharmacology, Severi Square, 1, S. b-Catenin is a key component of the Wnt signaling pathway, Andrea delle Fratte, 06132 Perugia, Italy. E-mail address: oxana.bereshchenko@ unipg.it and its levels are tightly controlled via Gsk3b-mediated phos- The online version of this article contains supplemental material. phorylation and ubiquitin-mediated degradation (16, 17). Phos- phorylated b-catenin, but not the nonphosphorylated form, is Abbreviations used in this article: BM, bone marrow; ChIP, chromatin immunopre- cipitation; DN, double-negative; DP, double-positive; EAE, experimental autoim- rapidly degraded by the ubiquitin–proteasome pathway. Activation mune encephalomyelitis; qPCR, quantitative real-time PCR; SP, single-positive; of the Wnt pathway, as well as the cancer-associated point mu- Tconv, conventional T; Treg, regulatory T; WT, wild-type. tations in the Ctnnb1 gene, prevents phosphorylation-dependent Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 degradation of b-catenin and triggers the accumulation of b-catenin www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700247 3032 Wnt/b-CATENIN IN T CELLS AND NEUROINFLAMMATION in the nucleus, where, in complex with its DNA-binding and forelimbs and combined forelimb and hindlimb grip strength in rodents, chromatin-modifying partners, it activates the transcription of including mice (36). In this study, the forelimb and hindlimb strength of the target genes (17, 18). In addition to its documented role in T cell mice was measured by gently lowering the mice over the top of the grid of the apparatus so that, in the first instance, only their forelimbs touched the development (19–25), a role for Wnt/b-catenin in T effector and grid, and in the second instance, their front and hind paws could grip the regulatory cell function is emerging. It was shown to inhibit grid. The torso was kept parallel to the grid, and the mouse was gently T cell activation (26), promote Th2 and Th17 differentiation (27, pulled back steadily until the grip was released down the complete length 28), and either promote (29, 30) or inhibit (28, 31) the function of the grid. The maximal grip strength value of the mice was displayed on the screen. The average of three trials in each condition was taken into of Treg cells. However, the causative role of Wnt/b-catenin in consideration. initiating autoimmune and inflammatory diseases of the CNS has not been demonstrated. Footprint test In this article, we demonstrate that stable b-catenin over- We assessed motor dysfunction using the footprint test, as described pre- expression in mice results in aberrant T cell activation, Th1 viously (37). Mice were encouraged to
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