TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation

Indumathi Manoharan, Yuan Hong, Amol Suryawanshi, Melinda L. Angus-Hill, Zuoming Sun, Andrew L. Mellor, David H. Munn, Santhakumar Manicassamy

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1, which recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. In this study, we show that TLR2 signaling via AKT activates the β-catenin/T cell factor 4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/T cell factor 4 was critical to induce regulatory molecules IL-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress proinflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive Th17/Th1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from Th17/Th1-mediated autoimmune neuroinflammation. Thus, activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.

Original languageEnglish (US)
Pages (from-to)4203-4213
Number of pages11
JournalJournal of Immunology
Volume193
Issue number8
DOIs
StatePublished - Oct 15 2014

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Catenins
Autoimmunity
Dendritic Cells
Inflammation
Transcription Factor 7-Like 2 Protein
Toll-Like Receptor 2
Zymosan
Cell Differentiation
Retinaldehyde
Th17 Cells
Th1 Cells
Adaptive Immunity
Vitamin A
Innate Immunity
Interleukin-10
Immunity
Oxidoreductases
Cytokines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. / Manoharan, Indumathi; Hong, Yuan; Suryawanshi, Amol; Angus-Hill, Melinda L.; Sun, Zuoming; Mellor, Andrew L.; Munn, David H.; Manicassamy, Santhakumar.

In: Journal of Immunology, Vol. 193, No. 8, 15.10.2014, p. 4203-4213.

Research output: Contribution to journalArticle

Manoharan, Indumathi ; Hong, Yuan ; Suryawanshi, Amol ; Angus-Hill, Melinda L. ; Sun, Zuoming ; Mellor, Andrew L. ; Munn, David H. ; Manicassamy, Santhakumar. / TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. In: Journal of Immunology. 2014 ; Vol. 193, No. 8. pp. 4203-4213.
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