Canonical Wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation

Amol Suryawanshi, Indumathi Manoharan, Yuan Hong, Daniel Swafford, Tanmay Majumdar, M. Mark Taketo, Balaji Manicassamy, Pandelakis A. Koni, Muthusamy Thangaraju, Zuoming Sun, Andrew L. Mellor, David H. Munn, Santhakumar Manicassamy

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3295-3304
Number of pages10
JournalJournal of Immunology
Volume194
Issue number7
DOIs
StatePublished - Apr 1 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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