Kynurenine acts as a signaling molecule to attenuate pulmonary fibrosis by enhancing the AHR-PTEN axis

作者：Yi Wang, Guorao Wu, Huihui Yue, Qing Zhou, Lei Zhang, Long He, Weikuan Gu, Rongfen Gao, Lingli Dong, Huilan Zhang, Jianping Zhao, Xiansheng Liu, Weining Xiong, Cong‐Yi Wang · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.06.017 · 被引用次数：26 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Tryptophan and brain disorders、Inflammatory Myopathies and Dermatomyositis

INTRODUCTION: Pulmonary fibrosis (PF) is a fatal fibrotic lung disease without any options to halt disease progression. Feasible evidence suggests that aberrant metabolism of amino acids may play a role in the pathoetiology of PF. However, the exact impact of kynurenine (Kyn), a metabolite derived from tryptophan (Trp) on PF is yet to be addressed. OBJECTIVES: This study aims to elucidate the role of kynurenine in both the onset and advancement of PF. METHODS: Liquid chromatography-tandem mass spectrometry was employed to assess Kyn levels in patients with idiopathic PF and PF associated with Sjögren's syndrome. Additionally, a mouse model of PF induced by bleomycin was utilized to study the impact of Kyn administration. Furthermore, cell models treated with TGF-β1 were used to explore the mechanism by which Kyn inhibits fibroblast functions. RESULTS: We demonstrated that high levels of Kyn are a clinical feature in both idiopathic PF patients and primary Sjögren syndrome associated PF patients. Further studies illustrated that Kyn served as a braking molecule to suppress fibroblast functionality, thereby protecting mice from bleomycin-induced lung fibrosis. The protective effects depend on AHR, in which Kyn induces AHR nuclear translocation, where it upregulates PTEN expression to blunt TGF-β mediated AKT/mTOR signaling in fibroblasts. However, in fibrotic microenviroment, the expression of AHR is repressed by methyl-CpG-binding domain 2 (MBD2), a reader interpreting the eff...