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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.

Author information

1
Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.
2
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
3
Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
4
Brigham and Women's Hospital, Boston, MA, USA.
5
Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC, USA.
6
Weill Cornell Medicine Pulmonary and Critical Care Medicine, New York, NY, USA.
7
Molecular Microbiology and Immunology, Brown University, Providence, RI, USA jack_elias@brown.edu.
8
Division of Medicine and Biological Sciences, Brown University, Warren Alpert School of Medicine, Providence, RI, USA.
9
Molecular Microbiology and Immunology, Brown University, Providence, RI, USA chun_lee@brown.edu.

Abstract

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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