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TGF-β1 is a critical mediator of tissue fibrosis in health and disease whose effects are augmented by chitinase 1 (CHIT1). However, the mechanisms that CHIT1 uses to regulate TGF-β1–mediated fibrotic responses have not been defined. Here, we demonstrate that CHIT1 enhances TGF-β1–stimulated fibrotic cellular and tissue responses and TGF-β1 signaling. Importantly, we also demonstrate that these effects are mediated by the ability of CHIT1 to inhibit TGF-β1 induction of its feedback inhibitor, SMAD7. CHIT1 also interacted with TGF-β receptor associated protein 1 (TGFBRAP1) and forkhead box O3 (FOXO3) with TGFBRAP1 playing a critical role in CHIT1 enhancement of TGF-β1 signaling and effector responses and FOXO3 playing a critical role in TGF-β1 induction of SMAD7. These pathways were disease relevant because the levels of CHIT1 were increased and inversely correlated with SMAD7 in tissues from patients with idiopathic pulmonary fibrosis or scleroderma-associated interstitial lung disease. These studies demonstrate that CHIT1 regulates TGF-β1/SMAD7 axis via TGFBRAP1 and FOXO3 and highlight the importance of these pathways in the pathogenesis of pulmonary fibrosis.

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.