Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
Am J Respir Cell Mol Biol. 2021 Nov;65(5):489-499. doi: 10.1165/rcmb.2020-0499OC.
The Wnt/β-catenin pathway initiates a signaling cascade that is critical in cell differentiation and the normal development of multiple organ systems. The reactivation of this pathway has been documented in experimental and human idiopathic pulmonary fibrosis, 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 noncanonical Wnt ligands remains unclear. This study showed significantly higher levels of Wnt11 expression in cells from both patients with idiopathic pulmonary fibrosis and bleomycin-treated mice, as well as in TGFβ-treated mouse lung fibroblasts. Moreover, Wnt11 induced myofibroblast differentiation as manifested by increased α-SMA (ACTA2) 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 N-terminal kinase)/c-Jun signaling and was inhibited by a JNK inhibitor. The potential importance of this signaling pathway was supported by evidence showing significantly increased levels of Wnt11 and activated JNK in the 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 noncanonical Wnt induction of myofibroblast differentiation mediated by the JNK/c-Jun pathway might play a significant role in pulmonary fibrosis, in addition to or in synergy with canonical Wnt3a/β-catenin signaling. Moreover, Wnt3a activation of noncanonical Wnt signaling might trigger a switch from canonical to noncanonical Wnt signaling to induce myofibroblast differentiation.
Wnt/β-catenin 通路起始一个信号级联反应，这对细胞分化和多个器官系统的正常发育至关重要。该通路的重新激活已在实验性和特发性肺纤维化的人类中得到证实，其中 Wnt/β-catenin 的激活与上皮细胞修复有关。此外，已知经典配体 Wnt3a 可诱导成肌纤维细胞分化；然而，非经典 Wnt 配体的作用仍不清楚。本研究表明，特发性肺纤维化患者和博莱霉素处理的小鼠的细胞以及 TGFβ 处理的鼠肺成纤维细胞中，Wnt11 的表达水平显著升高。此外，Wnt11 诱导的成肌纤维细胞分化表现为 α-SMA（ACTA2）表达增加，这与经典 Wnt3a/β-catenin 信号诱导的相似。进一步研究表明，Wnt11 诱导的 α-SMA 与 JNK（c-Jun N 末端激酶）/c-Jun 信号的激活有关，并且被 JNK 抑制剂抑制。该信号通路的潜在重要性得到了以下证据的支持：在博莱霉素诱导的肺纤维化小鼠的肺中，Wnt11 和激活的 JNK 的水平显著增加。有趣的是，成纤维细胞不表达经典 Wnt3a，但用外源性 Wnt3a 处理这些细胞会诱导内源性 Wnt11 和 Wnt5a，从而抑制 Wnt3a/β-catenin 靶基因 Axin2。这些发现表明，JNK/c-Jun 通路介导的非经典 Wnt 诱导的成肌纤维细胞分化可能在肺纤维化中发挥重要作用，除了或与经典 Wnt3a/β-catenin 信号协同作用。此外，Wnt3a 对非经典 Wnt 信号的激活可能引发从经典到非经典 Wnt 信号的转换，从而诱导成肌纤维细胞分化。
