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

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