Modulation of Inflammatory Responses by Wnt/β-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer

Abstract

The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway critical for several biological processes. An aberrant Wnt/β-catenin signaling is linked to several human diseases. Emerging studies have highlighted the regulatory role of the Wnt/β-catenin signaling pathway in normal physiological processes of parenchymal and hematopoietic cells. Recent studies have shown that the activation of Wnt/β-catenin pathway in dendritic cells (DCs) play a critical role in mucosal tolerance and suppression of chronic autoimmune pathologies. Alternatively, tumors activate Wnt/β-catenin pathway in DCs to induce immune tolerance and thereby evade antitumor immunity through suppression of effector T cell responses and promotion of regulatory T cell responses. Here, we review our work and current understanding of how Wnt/β-catenin signaling in DCs shapes the immune response in cancer and autoimmunity and discuss how Wnt/β-catenin pathway can be targeted for successful therapeutic interventions in various human diseases.

WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice

“…Our results strongly suggest that in the mouse model of LPS-induced endotoxemia, the net contribution of WNT proteins to systemic cytokine responses is pro-inflammatory. In contrast to the current paradigm of antiinflammatory functions of WNT/b-catenin signaling in the context of microbial stimulation, 39 our data indicate that b-catenin/ CBP-interactions enhance LPS-driven pro-inflammatory cytokine responses in vivo. This supports the notion that WNT-mediated b-catenin activity may also exert pro-inflammatory effects.…”

“…In this context, it is important to note that b-catenin stabilization is not exclusively triggered by WNT ligands and can be driven by hepatic growth factor and microbial ligands. 39,45,46 Thus, combined approaches targeting both endogenous WNT ligands as well as b-catenin activity, as employed here, should deliver refined insights into the contributions of WNT ligands and b-catenin signaling to inflammation and tissue pathology in complex in vivo settings. …”

Beta‐catenin promotes macrophage‐mediated acute inflammatory response after myocardial infarction

“…The role of b-catenin-mediated signaling in modulation of inflammation has received more attention in recent years. 24 Other potential mechanisms by which b-catenin regulates inflammation, including crosstalk between b-catenin and NF-jB signaling, may also be possible. 14 Interestingly, b-catenin-mediated signaling can inhibit inflammation through distinct mechanisms.…”

Interaction between the Wnt/β‐catenin signaling pathway and the EMMPRIN/MMP‐2, 9 route in periodontitis

“…A recent study indicated that EMMPRIN is a regulator of the Wnt/β‐catenin signaling pathway to accelerate lung tumorigenesis . Moreover, accumulated evidence indicates that the Wnt signaling pathway functions as an inflammatory signaling pathway, 1 typical example is in pulmonary fibrosis . Thus, we speculated there was a correlation between inflammation, Wnt/β‐catenin signaling pathway, MMPs and EMMPRIN.…”