The Immunomodulatory Capacity of Wnt on Human Dendritic Cells – Wnt/β-Catenin Signalling as a Potential Target for Bronchial Asthma

Bronchial asthma is a chronic heterogeneous syndrome which presents itself with several clinical and immunological phenotypes with a largely unknown pathogenesis. Current treatments have a variable effectiveness in patients and can only attenuate symptoms but not cure the disease. Detailed insights in pathomechanisms and regulatory processes could help to identify new therapeutic approaches. Recently, we identified the Wnt pathway, classically associated with embryogenesis and repair processes, as a potential therapeutic target with beneficial immunomodulatory effects in allergic asthma (Reuter; JI 2015; Beckert; JI 2018). In murine in vivo models Wnt-1 was able to suppress the development of allergic airway diseases and showed an anti-inflammatory effect. Since the immunoregulatory effects of Wnt ligands in humans are largely unknown we compared the suppressive properties of canonical Wnt-1 and non-canonical Wnt-5a in murine and human allergen specific dendritic cell/T cell interaction in vitro models, which simulate an immunological key event in bronchial asthma. Since the biological consequences of observed in vivo results are unclear immunofunctional assays were set up in vitro. In the murine studies DC were generated from bone marrow cells, incubated with the model allergen OVA, treated with or without Wnt ligands and activated with the TLR-4 ligand LPS. In the human model DC cultivated from blood monocytes derived from allergic donors (HDM CAP class > 4), were treated with or without Wnt ligands and activated. Subsequently, DC were cultivated with CFSE labelled allergen specific CD4⁺ T cells in the murine model, or CFSE labelled autologous donor CD4⁺ T cells in the human model. In both, the human and murine model, we could observe that canonical Wnt-1 was able to supress allergen specific proliferation and cytokine secretion of T cells. Wnt-5a demonstrated in comparison to Wnt-1 a comparable effectiveness in the murine and failed to supress the T cell response in the human model. The immunomodulatory capacity of Wnt1 seems to be transferable from mice to men. Manipulation of canonical Wnt signaling could be an interesting therapeutic target, especially for diseases with excessive DC mediated immune reactions.