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

ABSTRACT: TGF-?1 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-?1-mediated fibrotic responses have not been defined. Here, we demonstrate that CHIT1 enhances TGF-?1-stimulated fibrotic cellular and tissue responses and TGF-?1 signaling. Importantly, we also demonstrate that these effects are mediated by the ability of CHIT1 to inhibit TGF-?1 induction of its feedback inhibitor, SMAD7. CHIT1 also interacted with TGF-? receptor associated protein 1 (TGFBRAP1) and forkhead box O3 (FOXO3) with TGFBRAP1 playing a critical role in CHIT1 enhancement of TGF-?1 signaling and effector responses and FOXO3 playing a critical role in TGF-?1 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-?1/SMAD7 axis via TGFBRAP1 and FOXO3 and highlight the importance of these pathways in the pathogenesis of pulmonary fibrosis.

SUBMITTER: Lee CM 

PROVIDER: S-EPMC6516052 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature