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Canonical Wnt Signaling in Dendritic Cells Regulates Th1/Th17 Responses and Suppresses Autoimmune Neuroinflammation

Lookup NU author(s): Emeritus Professor Andrew MellorORCiD

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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.

Publication metadata

Author(s): Suryawanshi A, Manoharan I, Hong Y, Swafford D, Majumdar T, Taketo MM, Manicassamy B, Koni PA, Thangaraju M, Sun Z, Mellor AL, Munn DH, Manicassamy S

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2015

Volume: 194

Issue: 7

Pages: 3295-3304

Online publication date: 20/02/2015

Acceptance date: 31/01/2015

ISSN (print): 0022-1759

ISSN (electronic): 1872-7905

Publisher: Elsevier

URL: http://dx.doi.org/10.4049/​jimmunol.1402691

DOI: 10.4049/​jimmunol.1402691

PubMed id: 25710911

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