TY - JOUR
T1 - Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice
AU - Sorcini, Daniele
AU - Bruscoli, Stefano
AU - Frammartino, Tiziana
AU - Cimino, Monica
AU - Mazzon, Emanuela
AU - Galuppo, Maria
AU - Bramanti, Placido
AU - Al-Banchaabouchi, Mumna
AU - Farley, Dominika
AU - Ermakova, Olga
AU - Britanova, Olga
AU - Izraelson, Mark
AU - Chudakov, Dmitry
AU - Biagioli, Michele
AU - Sportoletti, Paolo
AU - Flamini, Sara
AU - Raspa, Marcello
AU - Scavizzi, Ferdinando
AU - Nerlov, Claus
AU - Migliorati, Graziella
AU - Riccardi, Carlo
AU - Bereshchenko, Oxana
N1 - Copyright © 2017 by The American Association of Immunologists, Inc.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
KW - Animals
KW - Inflammation
KW - Integrin alpha4beta1
KW - Mice
KW - Mice, Knockout
KW - Spinal Cord
KW - Spinal Cord Diseases
KW - Th1 Cells
KW - Wnt Signaling Pathway
KW - beta Catenin
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.4049/jimmunol.1700247
DO - 10.4049/jimmunol.1700247
M3 - Article
C2 - 28939758
VL - 199
SP - 3031
EP - 3041
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 9
ER -