2. Academic Validation
  3. Kynurenine acts as a signaling molecule to attenuate pulmonary fibrosis by enhancing the AHR-PTEN axis

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

  • J Adv Res. 2024 Jun 19:S2090-1232(24)00254-6. doi: 10.1016/j.jare.2024.06.017.
Yi Wang 1,  Guo-Rao Wu 1,  Huihui Yue 1,  Qing Zhou 1,  Lei Zhang 1,  Long He 2,  Weikuan Gu 3,  Rongfen Gao 4,  Lingli Dong 4,  Huilan Zhang 1,  Jianping Zhao 1,  Xiansheng Liu 5,  Weining Xiong 6,  Cong-Yi Wang 7
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China.
  • 2 Department of Clinical Laboratory, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200011, China.
  • 3 Department of Orthopedic Surgery and BME-Campbell Clinic, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  • 4 Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China.
  • 5 Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China. Electronic address: doctorliu69@126.com.
  • 6 Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, National Health Commission Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China; Department of Respiratory and Critical Care Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 639 Zhizaoju Lu, Shanghai 200011, China. Electronic address: xiongdoctor@qq.com.
  • 7 Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China; Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, China; The Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: wangcy@tjh.tjmu.edu.cn.
PMID: 38906325 DOI: 10.1016/j.jare.2024.06.017
Abstract

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 effect of DNA methylation, which results in a significantly reduced sensitivity of Kyn to fibroblasts. Therefore, exogenous administration of Kyn substantially reversed established PF.

Conclusion: Our studies not only highlighted a critical role of Trp metabolism in PF pathogenesis, but also provided compelling evidence suggesting that Kyn could serve as a promising metabolite against PF.

Keywords

Fibroblasts; Indoleamine 2,3-dioxygenase 1; Kynurenine; Pulmonary fibrosis; Tryptophan.

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