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Life Sci Alliance. 2019 May 13;2(3). pii: e201900350. doi: 10.26508/lsa.201900350. Print 2019 Jun.

Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3.

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Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Brigham and Women's Hospital, Boston, MA, USA.
Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Weill Cornell Medicine Pulmonary and Critical Care Medicine, New York, NY, USA.
Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
Division of Medicine and Biological Sciences, Brown University, Warren Alpert School of Medicine, Providence, RI, USA.
Molecular Microbiology and Immunology, Brown University, Providence, RI, USA


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.

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