Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Republic of Korea.
Department of Internal Medicine, Konkuk University School of Medicine, Seoul 05030, Republic of Korea.
Biochem Biophys Res Commun. 2024 Dec 3;736:150836. doi: 10.1016/j.bbrc.2024.150836. Epub 2024 Oct 23.
Pulmonary fibrosis is a progressive lung condition characterized by the excessive activation of myofibroblasts. Transforming growth factor beta 1 (TGFβ1) plays a crucial role in the differentiation of fibroblasts into myofibroblasts. In addition, toll-like receptor 2 (TLR2), known for its role in immune responses, contributes to pulmonary fibrosis by promoting myofibroblast differentiation. However, the interplay between TGFβ1 and TLR2 signaling pathways in myofibroblast differentiation has remained elusive. In the present study, we investigated the involvement of TLR2 in TGFβ1-induced fibroblast differentiation into myofibroblasts using IMR-90 human pulmonary fibroblasts as a model cell line. We found that TLR2 activation induced myofibroblast differentiation by enhancing the expression of early growth response 1 (EGR1) via the mitogen-activated protein kinase (MAPK) signaling pathway. Elevated EGR1 levels were detected in the lung tissues of a bleomycin (BLM)-induced mouse model of pulmonary fibrosis. Moreover, the administration of tomaralimab, an antagonistic anti-TLR2 antibody, reduced the EGR1 expression and collagen deposition. Altogether, targeting the TLR2-EGR1 pathway could be a promising therapeutic approach for pulmonary fibrosis by blocking TGFβ1-induced myofibroblast differentiation.
肺纤维化是一种进行性肺部疾病，其特征是肌成纤维细胞过度激活。转化生长因子β 1（TGFβ1）在成纤维细胞向肌成纤维细胞分化中起关键作用。此外，Toll 样受体 2（TLR2）因其在免疫反应中的作用而闻名，通过促进肌成纤维细胞分化而导致肺纤维化。然而，TGFβ1 和 TLR2 信号通路在肌成纤维细胞分化中的相互作用仍不清楚。在本研究中，我们使用 IMR-90 人肺成纤维细胞作为模型细胞系，研究了 TLR2 在 TGFβ1 诱导的成纤维细胞向肌成纤维细胞分化中的作用。我们发现 TLR2 激活通过丝裂原激活蛋白激酶（MAPK）信号通路诱导肌成纤维细胞分化，从而增强早期生长反应 1（EGR1）的表达。在博来霉素（BLM）诱导的肺纤维化小鼠模型的肺组织中检测到 EGR1 水平升高。此外，拮抗抗-TLR2 抗体 tomalimab 的给药降低了 EGR1 表达和胶原蛋白沉积。总的来说，通过阻断 TGFβ1 诱导的肌成纤维细胞分化，靶向 TLR2-EGR1 途径可能成为治疗肺纤维化的一种有前途的方法。
