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Abstract Number: 1144

Wnt Signaling Pathway Regulates Multi-Unconventional Differentiation and Function Of Human Dendritic Cells

Jia Wang1, Yi Liu2 and Yi Zhao2, 1General medical center, Sichuan Provincial People's Hospital, Chengdu, China, 2Department of Rheumatology and Immunology, West China Hospital of Sichuan University, Chengdu, China

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: dendritic cells and immune tolerance, WNT Signaling

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Session Information

Session Title: Innate Immunity and Rheumatic Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Dendritic cells (DCs) play a central role in regulating immune responses and govern T cell priming and polarization, mediating immunity and tolerance. Recent progress uncovered the Wnt signaling pathway is crucial for the immune balance and focuses on DCs as a direct target for their immunoregulatory role. In this study, we investigated the effect of the canonical and non-canonical Wnt signaling pathways regulate the differentiation and function of human DCs.

Methods:

Human peripheral blood CD14+ monocytes were cultured for 6 days with GM-CSF/IL-4 and then treated with LPS, Wnt3a, Wnt5a, GSK-3b inhibitor (SB216763) or silencing b-catenin for 24 h. Immunophenotypic characterizations of DCs were analyzed by flow cytometry. The supernatants were collected and cytokines (IL-17, IL-23, IL-10, TNF-¦Á, IFN-¦Ã) were assessed. Human peripheral blood and active rheumatoid arthritis patients’ synovial fluid CD3+ monocytes were isolated for mixed lymphocyte reaction. Proteins were extracted and incubated with antibodies against the total or phosphorylated forms of b-catenin, GSK-3b.

Results:

Our results showed that regulating the canonical and non-canonical Wnt signaling altered the maturation status and function of already differentiated DCs. The differentiation of DCs resulted in inhibiting activity of GSK-3b and stabilizing its substrate, b-catenin. GSK-3b inhibitor induced a full maturation phenotype of DCs that expressed mostly CD14. These DCs produced low levels of IL-17, IL-23 but high level of IL-10. Consequently, these DCs have a reduced capacity to stimulate Th17 differentiation and increased Th2 and Treg differentiation. The addition of Wnt3a or Wnt5a both increased CD1a+DCs but reduced CD83, CD80, CD86, CD40 and HLA-DR expression. Wnt3a-DCs produce scant amounts of cytokines and have a reduced capacity to stimulate all T cell subsets differentiation. Wnt5a-DCs produced low level of IL-17, TNF-¦Á while increased IL-23, IL-10 secretion and have an increased capacity to stimulate Th2 and Treg differentiation. b-catenin silencing reduced CD83 expression on LPS-induced DCs maturation and IL-10 secretion, without significant effect on capacity of DCs to stimulate T cells differentiation.

Conclusion:

Wnt signaling pathway regulates multi-unconventional differentiation and function of human DCs. GSK-3b inhibitor could induce terminal differentiation DCs into unconventional phenotypic maturation of DCs with tolerogenic features. Silencing of b-catenin partly impair LPS induced maturation of DCs. Exogenous Wnt3a inhibited maturation and function of DCs while Wnt5a inhibited maturation of DCs with regulatory features.

 


Disclosure:

J. Wang,
None;

Y. Liu,
None;

Y. Zhao,
None.

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