Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Front Immunol. 2018 Aug 6;9:1776. doi: 10.3389/fimmu.2018.01776. eCollection 2018.
S100A4, a calcium-binding protein, can promote pulmonary fibrosis fibroblast activation. Due partly to its various cellular origins, the exact role of S100A4 in the development of lung fibrosis remains elusive. Here, we show that in the bronchoalveolar lavage fluid, numbers of S100A4 macrophages correlated well with S100A4 protein levels and occurrence of idiopathic pulmonary fibrosis (IPF) in patients. A mouse model of bleomycin-induced pulmonary fibrosis demonstrated S100A4 macrophages as main source for extracellular S100A4 in the inflammatory phase. studies revealed that extracellular S100A4 could activate both mouse and human lung fibroblasts by upregulation of α-SMA and type I collagen, during which sphingosine-1-phosphate (S1P) increased. Inhibiting the S1P receptor subtypes S1P/S1P abrogated fibroblast activation. Accordingly, absence or neutralization of S100A4 significantly attenuated bleomycin-induced lung fibrosis . Importantly, adoptive transfer of S100A4 but not of S100A4 macrophages installed experimental lung injury in S100A4 mice that were otherwise not sensitive to fibrosis induction. Taken together, S100A4 released by macrophages promotes pulmonary fibrosis through activation of lung fibroblasts which is associated with S1P. This suggests that extracellular S100A4 or S100A4 macrophages within the lung as promising targets for early clinical diagnosis or therapy of IPF.
S100A4 是一种钙结合蛋白，可促进肺纤维化成纤维细胞的激活。由于其具有多种细胞起源，因此 S100A4 在肺纤维化发展中的确切作用仍不清楚。在这里，我们表明在支气管肺泡灌洗液中，S100A4 巨噬细胞的数量与 S100A4 蛋白水平以及特发性肺纤维化（IPF）患者的发生密切相关。博来霉素诱导的肺纤维化小鼠模型显示 S100A4 巨噬细胞是炎症期细胞外 S100A4 的主要来源。进一步的研究表明，细胞外 S100A4 可以通过上调α-SMA 和 I 型胶原激活小鼠和人肺成纤维细胞，在此期间，鞘氨醇-1-磷酸（S1P）增加。抑制 S1P 受体亚型 S1P/S1P 可阻断成纤维细胞的激活。因此，缺失或中和 S100A4 可显著减轻博来霉素诱导的肺纤维化。重要的是，S100A4 而非 S100A4 巨噬细胞的过继转移在 S100A4 小鼠中建立了实验性肺损伤，而这些小鼠对纤维化诱导不敏感。总之，巨噬细胞释放的 S100A4 通过激活肺成纤维细胞促进肺纤维化，这与 S1P 有关。这表明肺内细胞外 S100A4 或 S100A4 巨噬细胞是早期临床诊断或治疗 IPF 的有希望的靶点。
