Non-canonical Wnt Signaling Promotes Myofibroblast Differentiation in Pulmonary Fibrosis.
2021
The Wnt/β-catenin pathway initiates a signaling cascade critical in cell differentiation and normal development of multiple organ systems. The reactivation of this pathway has been documented in experimental and human idiopathic pulmonary fibrosis (IPF), wherein Wnt/β-catenin activation has been implicated in epithelial cell repair. Furthermore the canonical ligand Wnt3a is known to induce myofibroblast differentiation, however the role of non-canonical Wnt ligands remains unclear. This study showed significantly higher levels of Wnt11 expression in cells from both IPF patients and bleomycin-treated mice, as well as in TGFβ treated mouse lung fibroblasts. Moreover Wnt11 induced myofibroblast differentiation as manifested by increased α-smooth muscle actin (α-SMA) expression, which was similar to that induced by canonical Wnt3a/β-catenin signaling. Further investigation revealed that Wnt11 induction of α-SMA, was associated with the activation of JNK/c-Jun signaling and inhibited by a JNK inhibitor. The potential importance of this signaling pathway was supported by in vivo evidence showing significantly increased levels of Wnt11 and activated JNK in lungs of mice with bleomycin induced pulmonary fibrosis. Interestingly, fibroblasts did not express canonical Wnt3a but treatment of these cells with exogenous Wnt3a induced endogenous Wnt11 and Wnt5a resulting in repression of the Wnt3a/β-catenin target gene Axin2. These findings suggested that the non-canonical Wnt induction of myofibroblast differentiation mediated by JNK/c-Jun pathway might play a significant role in pulmonary fibrosis, in addition to, or synergy with canonical Wnt3a/β-catenin signaling. Moreover Wnt3a activation of non-canonical Wnt signaling might trigger a switch from canonical to non-canonical Wnt signaling to induce myofibroblast differentiation.
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