PDF(Pubmed)
Abstract：
The β-catenin dependent canonical Wnt signaling pathway plays a crucial role in maintaining normal homeostasis. However, when dysregulated, Wnt signaling is closely associated with various pathological conditions, including inflammation and different types of cancer.Here, we show a new connection between the leukocyte inflammatory response and the Wnt signaling pathway. Specifically, we demonstrate that circulating human primary monocytes express distinct Wnt signaling components and are susceptible to stimulation by the classical Wnt ligand-Wnt-3a. Although this stimulation increased the levels of β-catenin protein, the expression of the classical Wnt-target genes was not affected. Intriguingly, treating circulating human monocytes with Wnt-3a induces the secretion of cytokines and chemokines, enhancing monocyte migration. Mechanistically, the enhanced monocyte migration in response to Wnt stimuli is mediated through CCL2, a strong monocyte-chemoattractant.To further explore the physiological relevance of these findings, we conducted ex-vivo experiments using blood samples of patients with rheumatic joint diseases (RJD) - conditions where monocytes are known to be dysfunctional. Wnt-3a generated a unique cytokine expression profile, which was significantly distinct from that observed in monocytes obtained from healthy donors.Thus, our results provide the first evidence that Wnt-3a may serve as a potent stimulator of monocyte-driven immune processes. These findings contribute to our understanding of inflammatory diseases and, more importantly, shed light on the role of a core signaling pathway in the circulation.
摘要：
β-catenin依赖的经典Wnt信号通路在维持正常的稳态中起着至关重要的作用。然而,当失调时，Wnt信号与各种病理状况密切相关，包括炎症和不同类型的癌症。这里,我们显示了白细胞炎症反应与Wnt信号通路之间的新联系。具体来说,我们证明了循环的人原代单核细胞表达不同的Wnt信号传导成分，并且对经典的Wnt配体-Wnt-3a的刺激敏感。虽然这种刺激增加了β-连环蛋白的水平，经典Wnt靶基因的表达不受影响。有趣的是，用Wnt-3a处理循环人单核细胞诱导细胞因子和趋化因子的分泌，增强单核细胞迁移。机械上,响应Wnt刺激的增强的单核细胞迁移是通过CCL2(一种强单核细胞化学引诱物)介导的。为了进一步探索这些发现的生理相关性，我们使用风湿性关节病（RJD）患者的血液样本进行了离体实验-已知单核细胞功能失调。Wnt-3a产生了独特的细胞因子表达谱，这与从健康供体获得的单核细胞中观察到的明显不同。因此，我们的研究结果为Wnt-3a可能作为单核细胞驱动的免疫过程的强效刺激物提供了第一个证据.这些发现有助于我们对炎症性疾病的理解，更重要的是,阐明了核心信号通路在循环中的作用。
