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.

中文翻译：

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几丁质酶 1 通过 TGFBRAP1 和 FOXO3 调节 TGF-β/SMAD7 通路来调节肺纤维化。


TGF-β1 是健康和疾病中组织纤维化的关键介质，几丁质酶 1 (CHIT1) 可以增强其作用。然而，CHIT1 用于调节 TGF-β1 介导的纤维化反应的机制尚未明确。在这里，我们证明 CHIT1 增强 TGF-β1 刺激的纤维化细胞和组织反应以及 TGF-β1 信号传导。重要的是，我们还证明这些效应是由 CHIT1 抑制 TGF-β1 诱导其反馈抑制剂 SMAD7 的能力介导的。 CHIT1 还与 TGF-β 受体相关蛋白 1 (TGFBRAP1) 和叉头盒 O3 (FOXO3) 相互作用，其中 TGFBRAP1 在 CHIT1 增强 TGF-β1 信号传导和效应反应中发挥关键作用，而 FOXO3 在 TGF-β1 诱导SMAD7。这些通路与疾病相关，因为在特发性肺纤维化或硬皮病相关间质性肺病患者的组织中，CHIT1 水平升高，且与 SMAD7 呈负相关。这些研究表明 CHIT1 通过 TGFBRAP1 和 FOXO3 调节 TGF-β1/SMAD7 轴，并强调了这些途径在肺纤维化发病机制中的重要性。