The Canonical but Not the Noncanonical Wnt Pathway Inhibits the Development of Allergic Airway Disease

Abstract

Asthma is a syndrome with multifactorial causes, resulting in a variety of different phenotypes. Current treatment options are not curative and are sometimes ineffective in certain disease phenotypes. Therefore, novel therapeutic approaches are required. Recent findings have shown that activation of the canonical Wnt signaling pathway suppresses the development of allergic airway disease. In contrast, the effect of the noncanonical Wnt signaling pathway activation on allergic airway disease is not well described. The aim of this study was to validate the therapeutic effectiveness of Wnt-1-driven canonical Wnt signaling compared with Wnt-5a-driven noncanonical signaling in murine models. In vitro, both ligands were capable of attenuating allergen-specific T cell activation in a dendritic cell-dependent manner. In addition, the therapeutic effects of Wnt ligands were assessed in two different models of allergic airway disease. Application of Wnt-1 resulted in suppression of airway inflammation as well as airway hyperresponsiveness and mucus production. In contrast, administration of Wnt-5a was less effective in reducing airway inflammation or goblet cell metaplasia. These results suggest an immune modulating function for canonical as well as noncanonical Wnt signaling, but canonical Wnt pathway activation appears to be more effective in suppressing allergic airway disease than noncanonical Wnt activation.

WNT Signalling in Lung Physiology and Pathology

“…Moreover, eosinophils isolated from asthma patients activate WNT5A gene expression in airway smooth muscle more than eosinophils obtained from healthy subjects (Januskevicius et al 2016). In contrast, whole lung application of recombinant WNT-5A does not impact on allergic inflammation, whereas application of recombinant WNT-1 represses Th2 dependent inflammation in a mouse model of asthma (Beckert et al 2018), possibly indicating distinct roles for WNT/β-catenin-dependent (protective) and WNT/β-catenin-independent (detrimental) signalling in the development of asthma, or for cell-specific roles of WNT signalling in individual features of the disease. The latter possibility seems most likely as WNT/β-catenin-dependent signalling is not protective towards all features of asthma and induces both β-catenin stabilization and the secretion of proinflammatory cytokines such as IL-8 and CCL8 from human mast cells.…”

Functions of the WNT Signaling Network in Shaping Host Responses to Infection

“…The impact of exogenously added or endogenously released WNT ligands and contributions of β-catenin signaling on the expression of functional surface markers of DCs (e.g., MHC-I and MHC-II, co-stimulatory molecules, PD-L1, PD-L2) and DC endocytic capacity has been analyzed in a number of studies returning varying results (115, 137, 174–182). Such variability is likely governed by the use of cells from different species; differentiation and culture conditions; use of exogenous modulation through recombinant WNTs, conditioned media, WNT regulators vs. perturbation of endogenous WNT ligands and signaling events, for example by using small molecule inhibitors or genetic perturbations.…”

Candida albicans elicits protective allergic responses via platelet mediated T helper 2 and T helper 17 cell polarization

“…The Wnt-beta catenin signaling pathway is activated in allergic airway disease and regulates this phenotype in complex ways (Kwak et al, 2015). A primary outcome of Wnt activation appears to be suppression of allergic airway disease (Beckert et al, 2018), although in the context of ultrafine particle challenge, Wnt activation may promote allergic disease (Harb et al, 2020). A suppressive role for Wnt was confirmed by the demonstration that Dkk-1 was required for allergic airway disease due to house dust mite (HDM) allergen (Chae et al, 2016b).…”