The Wnt/β-Catenin Pathway Attenuates Experimental Allergic Airway Disease

Abstract

Signaling via the Wnt/β-catenin pathway plays crucial roles in embryogenesis and homeostasis of adult tissues. In the lung, the canonical Wnt/β-catenin pathway has been implicated in remodeling processes, development of emphysema, and fibrosis. However, its relevance for the modulation of allergic responses in the lung remains unclear. Using genetically modified mice with lung-specific inducible (doxycycline) Wnt-1 expression (CCSP-rtTA × tetO-Wnt1), the impact of Wnt on the development of allergic airway disease was analyzed. Overexpression of Wnt during the allergen challenge phase attenuated the development of airway inflammation in an acute model, as well as in a more therapeutic model of secondary challenge. These findings were further supported by treatment of allergen-sensitized mice with LiCl during challenge. Similar to Wnt, LiCl prevented the degradation of β-catenin and, thus, attenuated allergic airway inflammation and hyperresponsiveness. Migration studies revealed that lung-specific expression of Wnt reduced the migration of Ag-loaded dendritic cells (DCs) into the draining lymph nodes following allergen challenge. Administration of in vitro allergen-loaded DCs overcame Wnt-mediated suppression of airway inflammation. Furthermore, in vitro studies confirmed that DC-dependent T cell activation is impaired by blocking β-catenin degradation. These results demonstrate an important role for the canonical Wnt/β-catenin pathway in the DC-mediated regulation of allergic responses in the lung.

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

“…38 Furthermore, coculture of Wnt-treated DC with naïve T cells resulted in the induction of FoxP3-expressing regulatory T cells 38 and also exposure to Wnt1 markedly reduced the activation of effector T cells by DCs in coculture experiments. 39 Similar results were observed in a human cell coculture system. Exposure to Wnt5a resulted in increased secretion of IL-10 in blood-derived monocytes.…”

“…67 In addition, recent studies using LiCl in a murine model of allergic airway disease showed that treatment of sensitized animals before and during allergen challenge with LiCl reduced airway inflammation, hyperresponsiveness, and mucus production. 39 These finding add a mechanistic explanation to the observed effects in humans.…”

“…Indeed, induction of Wnt1 before and during airway challenges reduced airway inflammation and airway hyperreactivity, both hallmarks of allergic asthma. 39 These effects were detectable in prophylactic situation (increased Wnt expression before the first development of allergic airway disease) and also in a therapeutic context (increased Wnt expression in developed airway disease). Further analysis of the immunological responses showed no change in the proportion of regulatory T cells in lymph nodes or in lung tissue.…”

“…Both overexpression of Wnt1 in the airways and treatment with LiCl resulted in diminished goblet cell metaplasia. 39 Particularly, the increase of smooth muscle mass induced by cellular hyperplasia and hypertrophy is responsible for chronic airflow limitation and increased bronchial hyperresponsiveness. Interestingly, Wnt/β-catenin signaling is involved in proliferation of ASM in vivo and in vitro.…”

The Varieties of Immunological Experience: Of Pathogens, Stress, and Dendritic Cells

“…Consistent with this, a recent study demonstrated that glycans associated with the mucin MUC2 in the gut imprinted DCs with tolerogenic properties via activation of β-catenin (144). Furthermore, a recent study has demonstrated a role for β-catenin in regulating DC function in the lung by blocking the migration of DCs from the lung to the draining LN and programming suppressive properties on such DCs (257).…”