Sung Eun-Ah, Dozmorov Mikhail G, Song SuJeong, Aung Theingi, Park Min Hee, Sime Patricia J, Chae Wook-Jin
Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
FEBS Lett. 2025 May;599(10):1468-1480. doi: 10.1002/1873-3468.15106. Epub 2025 Jan 28.
Tissue fibrosis is a progressive pathological process with excessive deposition of extracellular matrix proteins (ECM). Myofibroblasts, identified by alpha-smooth muscle actin (αSMA) expression, play an important role in tissue fibrosis by producing ECM. Here, we found that the Wnt antagonist Dickkopf1 (DKK1) induced gene expressions associated with inflammation and fibrosis in lung fibroblasts. We demonstrated that genetic deletion of LRP6, a receptor for Wnt ligands and DKK1, in αSMA-expressing cells using Acta2-cre Lrp6 (Lrp6) mice abrogated the bleomycin (BLM)-induced lung inflammation and fibrosis phenotype, suggesting an important role for LRP6 in modulating inflammation and fibrotic processes in the lung. Our results highlight the crucial role of LRP6 in fibroblasts in regulating inflammation and fibrosis upon BLM-induced lung injury.
组织纤维化是一种细胞外基质蛋白（ECM）过度沉积的进行性病理过程。通过α-平滑肌肌动蛋白（αSMA）表达鉴定的肌成纤维细胞，通过产生ECM在组织纤维化中发挥重要作用。在此，我们发现Wnt拮抗剂Dickkopf1（DKK1）诱导肺成纤维细胞中与炎症和纤维化相关的基因表达。我们证明，使用Acta2-cre Lrp6（Lrp6）小鼠在表达αSMA的细胞中基因敲除Wnt配体和DKK1的受体LRP6，可消除博来霉素（BLM）诱导的肺部炎症和纤维化表型，提示LRP6在调节肺部炎症和纤维化过程中起重要作用。我们的结果突出了LRP6在成纤维细胞中对BLM诱导的肺损伤后调节炎症和纤维化的关键作用。
