Wang Qian-Rong, Liu Suo-Si, Min Jia-Li, Yin Min, Zhang Yan, Zhang Yu, Tang Xiang-Ning, Li Xia, Liu Shan-Shan
National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
Biochem Pharmacol. 2023 Apr;210:115475. doi: 10.1016/j.bcp.2023.115475. Epub 2023 Mar 2.
Pulmonary fibrosis (PF) is a type of fatal respiratory diseases with limited therapeutic options and poor prognosis. The chemokine CCL17 plays crucial roles in the pathogenesis of immune diseases. Bronchoalveolar lavage fluid (BALF) CCL17 levels are significantly higher in patients with idiopathic PF (IPF) than in healthy volunteers. However, the source and function of CCL17 in PF remain unclear. Here, we demonstrated that the levels of CCL17 were increased in the lungs of IPF patients and mice with bleomycin (BLM)-induced PF. In particular, CCL17 were upregulated in alveolar macrophages (AMs) and antibody blockade of CCL17 protected mice against BLM-induced fibrosis and significantly reduced fibroblast activation. Mechanistic studies revealed that CCL17 interacted with its receptor CCR4 on fibroblasts, thereby activating the TGF-β/Smad signaling pathway to promote fibroblast activation and tissue fibrosis. Moreover, the knockdown of CCR4 by CCR4-siRNA or blockade by CCR4 antagonist C-021 was able to ameliorate PF pathology in mice. In summary, the CCL17-CCR4 axis is involved in the progression of PF, and targeting of CCL17 or CCR4 inhibits fibroblast activation and tissue fibrosis and may benefit patients with fibroproliferative lung diseases.
肺纤维化（PF）是一种致命的呼吸系统疾病，治疗选择有限且预后不良。趋化因子CCL17在免疫疾病的发病机制中起关键作用。特发性PF（IPF）患者支气管肺泡灌洗液（BALF）中的CCL17水平显著高于健康志愿者。然而，PF中CCL17的来源和功能仍不清楚。在此，我们证明IPF患者和博来霉素（BLM）诱导的PF小鼠肺中CCL17水平升高。特别是，CCL17在肺泡巨噬细胞（AMs）中上调，对CCL17进行抗体阻断可保护小鼠免受BLM诱导的纤维化，并显著降低成纤维细胞活化。机制研究表明，CCL17与其在成纤维细胞上的受体CCR4相互作用，从而激活TGF-β/Smad信号通路，促进成纤维细胞活化和组织纤维化。此外，用CCR4-siRNA敲低CCR4或用CCR4拮抗剂C-021阻断CCR4能够改善小鼠的PF病理。总之，CCL17-CCR4轴参与PF的进展，靶向CCL17或CCR4可抑制成纤维细胞活化和组织纤维化，可能使纤维增生性肺病患者受益。
