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Galectin-3 Interacts with the CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease.

Authors
  • Zhou, Yang1
  • He, Chuan Hua2
  • Yang, Daniel S2
  • Nguyen, Tung2
  • Cao, Yueming2
  • Kamle, Suchitra2
  • Lee, Chang-Min2
  • Gochuico, Bernadette R3
  • Gahl, William A3
  • Shea, Barry S4
  • Lee, Chun Geun2
  • Elias, Jack A1, 5
  • 1 Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912; [email protected] [email protected]
  • 2 Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912.
  • 3 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
  • 4 Division of Pulmonary, Critical Care and Sleep Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903; and.
  • 5 Department of Internal Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903.
Type
Published Article
Journal
The Journal of Immunology
Publisher
The American Association of Immunologists
Publication Date
Feb 02, 2018
Identifiers
DOI: 10.4049/jimmunol.1701442
PMID: 29427412
Source
Medline
License
Unknown

Abstract

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.

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