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

• Published in: Life science alliance 2019-06, Vol.2 (3)
• Main Authors: Lee, Chang-Min, He, Chuan-Hua, Park, Jin Wook, Lee, Jae Hyun, Kamle, Suchita, Ma, Bing, Akosman, Bedia, Cotez, Roberto, Chen, Emily, Zhou, Yang, Herzog, Erica L, Ryu, Changwan, Peng, Xueyan, Rosas, Ivan O, Poli, Sergio, Bostwick, Carol Feghali, Choi, Augustine M, Elias, Jack A, Lee, Chun Geun
• Format: Article
• Language: English
• Subjects: Fibroblasts - metabolism; Forkhead Box Protein O3 - metabolism; Gene Expression Regulation; Genes, Reporter; Hexosaminidases - genetics; Hexosaminidases - metabolism; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - metabolism; Promoter Regions, Genetic; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; RNA, Small Interfering - genetics; Signal Transduction; Smad7 Protein - metabolism; Transforming Growth Factor beta - metabolism
• ISSN: 2575-1077
• DOI: 10.26508/lsa.201900350

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.