TY - JOUR
T1 - Canonical Wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation
AU - Suryawanshi, Amol
AU - Manoharan, Indumathi
AU - Hong, Yuan
AU - Swafford, Daniel
AU - Majumdar, Tanmay
AU - Taketo, M. Mark
AU - Manicassamy, Balaji
AU - Koni, Pandelakis A.
AU - Thangaraju, Muthusamy
AU - Sun, Zuoming
AU - Mellor, Andrew L.
AU - Munn, David H.
AU - Manicassamy, Santhakumar
N1 - Publisher Copyright:
Copyright © 2015 by The American Association of Immunologists, Inc.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Breakdown in immunological tolerance to self-Ags or uncontrolled inflammation results in autoimmune disorders. Dendritic cells (DCs) play an important role in regulating the balance between inflammatory and regulatory responses in the periphery. However, factors in the tissue microenvironment and the signaling networks critical for programming DCs to control chronic inflammation and promote tolerance are unknown. In this study, we show that wnt ligand-mediated activation of β-catenin signaling in DCs is critical for promoting tolerance and limiting neuroinflammation. DC-specific deletion of key upstream (lipoprotein receptor-related protein [LRP]5/6) or downstream (β-catenin) mediators of canonical wnt signaling in mice exacerbated experimental autoimmune encephalomyelitis pathology. Mechanistically, loss of LRP5/6-β-catenin-mediated signaling in DCs led to an increased Th1/Th17 cell differentiation but reduced regulatory T cell response. This was due to increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines such as IL-10 and IL-27 by DCs lacking LRP5/6-β-catenin signaling. Consistent with these findings, pharmacological activation of canonical wnt/β-catenin signaling delayed experimental autoimmune encephalomyelitis onset and diminished CNS pathology. Thus, the activation of canonical wnt signaling in DCs limits effector T cell responses and represents a potential therapeutic approach to control autoimmune neuroinflammation.
AB - Breakdown in immunological tolerance to self-Ags or uncontrolled inflammation results in autoimmune disorders. Dendritic cells (DCs) play an important role in regulating the balance between inflammatory and regulatory responses in the periphery. However, factors in the tissue microenvironment and the signaling networks critical for programming DCs to control chronic inflammation and promote tolerance are unknown. In this study, we show that wnt ligand-mediated activation of β-catenin signaling in DCs is critical for promoting tolerance and limiting neuroinflammation. DC-specific deletion of key upstream (lipoprotein receptor-related protein [LRP]5/6) or downstream (β-catenin) mediators of canonical wnt signaling in mice exacerbated experimental autoimmune encephalomyelitis pathology. Mechanistically, loss of LRP5/6-β-catenin-mediated signaling in DCs led to an increased Th1/Th17 cell differentiation but reduced regulatory T cell response. This was due to increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines such as IL-10 and IL-27 by DCs lacking LRP5/6-β-catenin signaling. Consistent with these findings, pharmacological activation of canonical wnt/β-catenin signaling delayed experimental autoimmune encephalomyelitis onset and diminished CNS pathology. Thus, the activation of canonical wnt signaling in DCs limits effector T cell responses and represents a potential therapeutic approach to control autoimmune neuroinflammation.
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U2 - 10.4049/jimmunol.1402691
DO - 10.4049/jimmunol.1402691
M3 - Article
C2 - 25710911
AN - SCOPUS:84925868170
SN - 0022-1767
VL - 194
SP - 3295
EP - 3304
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -