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Review
. 2017:2017:3520581.
doi: 10.1155/2017/3520581. Epub 2017 May 9.

Distinct Roles of Wnt/ β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Juan Shi  1 , Feng Li  2 , Meihui Luo  1 , Jun Wei  1   2 , Xiaoming Liu  1   2
Affiliations
Review

Distinct Roles of Wnt/ β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Juan Shi et al. Mediators Inflamm. 2017.

Abstract

Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/β-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema. Intriguingly, Wnt/β-catenin signaling is activated in IPF; an inhibition of this signaling leads to an alleviation of pulmonary inflammation and fibrosis in experimental models. Conversely, Wnt/β-catenin signaling is inactivated in COPD tissues, and its reactivation results in an amelioration of airspace enlargement with a restored alveolar epithelial structure and function in emphysema models. These studies thus imply distinct mechanisms of Wnt/β-catenin signaling in the pathogenesis of these two chronic pulmonary diseases, indicating potential targets for COPD and IPF treatments. This review article aims to summarize the involvement and pathogenic roles of Wnt signaling pathways in the COPD and IPF, with a focus on the implication of Wnt/β-catenin signaling as underlying mechanisms and therapeutic targets in these two incurable diseases.

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Figures

Figure 1
Figure 1
Illustration of Wnt signaling cascades. Based on the dependence of β-catenin, Wnt signaling can be classified as β-catenin-dependent Wnt signaling pathway (canonical Wnt signaling pathway) and β-catenin-independent Wnt signaling pathway (noncanonical Wnt signaling pathway). In canonical Wnt signaling pathway, in the absence of Wnt ligand(s), cytoplasmic β-catenin is targeted for phosphorylation by a multiprotein complex comprised of Axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), and casein kinase 1α (CK1α). The phosphorylated form of β-catenin is recognized by an E3 ubiquitin ligase (β-TrCP) and then targeted for proteosomal degradation, resulting in low cytosolic levels (left panel); in the presence of Wnt ligand(s), Wnt ligand binds to a FZD and LRP coreceptors, which triggers a signaling cascade by activating Dvl. The activated Dvl inhibits GSK3β, which destroys the stability of the multiprotein complex and accordingly leads to the intracellular accumulation of cytosolic β-catenin. The stable and active β-catenin then translocates into the nucleus, in which it acts as a transcriptional coactivator with TCF/LEF to activate Wnt-responsive target genes (left panel). In a noncanonical Wnt signaling pathway, Wnt ligand (such as the Wnt5a, a typical noncanonical Wnt) binds to its receptor (FZD) and coreceptor (Ror1/2) and triggers noncanonical signaling cascades, which include the Wnt/calcium (Ca2+) and Wnt/planar cell polarity (PCP) pathways. In the Wnt/Ca2+ pathway (left panel), Wnt protein binds to FZD and Ror2 receptor and leads to activated G proteins, resulting in enhanced intracellular calcium level or decreased cGMP; the calcium/calmodulin-dependent protein kinase II (CaMKII) or protein kinase C (PKC) was then activated. In the Wnt/PCP pathway (right panel), the Wnt ligand binds to a FZD receptor on the cell surface, followed by activating Rho/Rac small GTPase and Jun N-terminal kinase (JNK) to assist with cytoskeletal organization and gene expression (right panel).
Figure 2
Figure 2
Scheme of possibly distinct pathogenic role of Wnt/β-catenin signaling in COPD and IPF. Possible mechanisms of Wnt/β-catenin signaling in the pathogenesis of COPD (right) and IPF (left) are proposed based on the literatures. In IPF, an enhanced Wnt/β-catenin signaling of epithelial cells interacts with TGF-β to promote EMT, which leads to mesenchymal overgrowth and fibrosis. On the other hand, activated Wnt signaling can increase the expression of Wnt target genes related to cell proliferation and ECM, which leads to bronchiolar overgrowth and honeycombing. In the case of COPD, a decreased Wnt/β-catenin signaling activity in the mesenchymal compartment results in the reduced expression of Wnt target genes related to cell proliferation, leading to mesenchymal deficiency and the reduction of ECM protein expression in alveolar cells, accordingly the development of emphysema or dysfunctions MSCs and immune regulations in small airway, which leads to enhance inflammation in airway.
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