Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912;
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912.
J Immunol. 2018 Mar 15;200(6):2140-2153. doi: 10.4049/jimmunol.1701442. Epub 2018 Feb 2.
Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in HPS-1 and HPS-4 patients. However, the mechanisms that underlie the exaggerated injury and fibroproliferative repair responses in HPS have not been adequately defined. In particular, although Galectin-3 (Gal-3) is dysregulated in HPS, its roles in the pathogenesis of HPS have not been adequately defined. In addition, although chitinase 3-like 1 (CHI3L1) and its receptors play major roles in the injury and repair responses in HPS, the ability of Gal-3 to interact with or alter the function of these moieties has not been evaluated. In this article, we demonstrate that Gal-3 accumulates in exaggerated quantities in bronchoalveolar lavage fluids, and traffics abnormally and accumulates intracellularly in lung fibroblasts and macrophages from bleomycin-treated pale ear, HPS-1-deficient mice. We also demonstrate that Gal-3 drives epithelial apoptosis when in the extracellular space, and stimulates cell proliferation and myofibroblast differentiation when accumulated in fibroblasts and M2-like differentiation when accumulated in macrophages. Biophysical and signaling evaluations also demonstrated that Gal-3 physically interacts with IL-13Rα2 and CHI3L1, and competes with TMEM219 for IL-13Rα2 binding. By doing so, Gal-3 diminishes the antiapoptotic effects of and the antiapoptotic signaling induced by CHI3L1 in epithelial cells while augmenting macrophage Wnt/β-catenin signaling. Thus, Gal-3 contributes to the exaggerated injury and fibroproliferative repair responses in HPS by altering the antiapoptotic and fibroproliferative effects of CHI3L1 and its receptor complex in a tissue compartment-specific manner.
Hermansky-Pudlak 综合征（HPS）是一组由突变引起的遗传性疾病，这些突变改变了溶酶体相关细胞器的功能。肺纤维化是 HPS-1 和 HPS-4 患者发病和死亡的主要原因。然而，HPS 中过度损伤和纤维增生性修复反应的机制尚未得到充分定义。特别是，虽然半乳糖凝集素-3（Gal-3）在 HPS 中失调，但它在 HPS 发病机制中的作用尚未得到充分定义。此外，尽管几丁质酶 3 样 1（CHI3L1）及其受体在 HPS 的损伤和修复反应中发挥主要作用，但 Gal-3 与这些分子相互作用或改变其功能的能力尚未得到评估。在本文中，我们证明 Gal-3 在博莱霉素处理的苍白耳 HPS-1 缺陷小鼠的支气管肺泡灌洗液中大量积累，并异常运输并在肺成纤维细胞和巨噬细胞中积累。我们还证明，Gal-3 在细胞外空间时会驱动上皮细胞凋亡，在成纤维细胞中积累时会刺激细胞增殖和肌成纤维细胞分化，在巨噬细胞中积累时会促进 M2 样分化。生物物理和信号评估还表明，Gal-3 与 IL-13Rα2 和 CHI3L1 物理相互作用，并与 TMEM219 竞争与 IL-13Rα2 的结合。通过这种方式，Gal-3 减弱了 CHI3L1 在上皮细胞中的抗凋亡作用及其诱导的抗凋亡信号，同时增强了巨噬细胞的 Wnt/β-catenin 信号。因此，Gal-3 通过改变 CHI3L1 及其受体复合物在组织隔室特异性的抗凋亡和促纤维增生作用，导致 HPS 中过度的损伤和纤维增生性修复反应。
