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Galectin-3 Interacts with CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease
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A5753 - Galectin-3 Interacts with CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease
Author Block: Y. Zhou1, C. He1, D. Yang1, T. Nguyen1, S. Kamle1, C. Lee1, B. Gochuico2, W. Gahl3, B. Shea4, C. G. Lee1, J. Elias5; 1Molecular Microbiology and Immunology, Brown University, Providence, RI, United States, 2Natl Inst of Hlth, Bethesda, MD, United States, 3Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, United States, 4Pulmonary, Critical Care and Sleep Medicine, Rhode Island Hospital, Providence, RI, United States, 5Warren Alpert Medical School, Brown University, Providence, RI, United States.
Rationale: Pulmonary fibrosis is the major cause of morbidity and mortality in Hermansky-Pudlak Syndrome (HPS) 1 and 4 patients. However, the mechanisms that underlie the exaggerated injury and fibroproliferative repair responses in HPS have not been adequately defined.
Objectives: To test the hypothesis that Galectin-3 (Gal-3) influences the injury and repair responses in HPS in a tissue-specific manner, via interactions with chitinase 3-like-1 (CHI3L1) and or its receptor components.
Methods: We characterized the levels of Gal-3 in BAL from bleomycin-treated wild type and HPS-1 deficient mice, characterized the expression and trafficking of Gal-3 in epithelial cells, fibroblasts and macrophages from these animals, and defined the effects of extracellular and intracellular Gal-3 on these cell populations. We also used biophysical approaches to define the interactions of Gal-3, CHI3L1 and components of its receptor complex.
Measurements and Main Results: We demonstrate that Gal-3 accumulates in bronchoalveolar lavage fluids and trafficks abnormally and accumulates intracellularly in lung fibroblasts and macrophages from bleomycin-treated 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 demonstrated that Gal-3 physically interacts with IL-13Rα2 and CHI3L1 and competes with TMEM219 for IL-13Rα2 binding.
Conclusions: 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.
Author Block: Y. Zhou1, C. He1, D. Yang1, T. Nguyen1, S. Kamle1, C. Lee1, B. Gochuico2, W. Gahl3, B. Shea4, C. G. Lee1, J. Elias5; 1Molecular Microbiology and Immunology, Brown University, Providence, RI, United States, 2Natl Inst of Hlth, Bethesda, MD, United States, 3Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, United States, 4Pulmonary, Critical Care and Sleep Medicine, Rhode Island Hospital, Providence, RI, United States, 5Warren Alpert Medical School, Brown University, Providence, RI, United States.
Rationale: Pulmonary fibrosis is the major cause of morbidity and mortality in Hermansky-Pudlak Syndrome (HPS) 1 and 4 patients. However, the mechanisms that underlie the exaggerated injury and fibroproliferative repair responses in HPS have not been adequately defined.
Objectives: To test the hypothesis that Galectin-3 (Gal-3) influences the injury and repair responses in HPS in a tissue-specific manner, via interactions with chitinase 3-like-1 (CHI3L1) and or its receptor components.
Methods: We characterized the levels of Gal-3 in BAL from bleomycin-treated wild type and HPS-1 deficient mice, characterized the expression and trafficking of Gal-3 in epithelial cells, fibroblasts and macrophages from these animals, and defined the effects of extracellular and intracellular Gal-3 on these cell populations. We also used biophysical approaches to define the interactions of Gal-3, CHI3L1 and components of its receptor complex.
Measurements and Main Results: We demonstrate that Gal-3 accumulates in bronchoalveolar lavage fluids and trafficks abnormally and accumulates intracellularly in lung fibroblasts and macrophages from bleomycin-treated 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 demonstrated that Gal-3 physically interacts with IL-13Rα2 and CHI3L1 and competes with TMEM219 for IL-13Rα2 binding.
Conclusions: 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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