Miao Yushan, Zhong Caiming, Bao Shujun, Wei Kunchen, Wang Wei, Li Na, Bai Chong, Chen Wei, Tang Hao
Department of Respiratory and Critical Care Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
Department of Respiratory and Critical Care Medicine, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
iScience. 2024 May 6;27(6):109923. doi: 10.1016/j.isci.2024.109923. eCollection 2024 Jun 21.
Previous researches indicate that tryptophan metabolism is critical to allergic inflammation and that indoleamine 2,3-dioxygenase 1 (IDO1), as a key enzyme, is known for its immunosuppressive properties. Therefore, we are aimed to explore whether tryptophan metabolism, especially IDO1, influences allergic asthma and clarify specific mechanism. With the analysis of clinical data, exploration in cell experiments, and verifying in HDM-induced asthma mice models, we finally found that in allergic asthma, low level of T1 cytokines along with high level of T2 cytokines inhibited the expression of IDO1 in airway epithelium, hampering the kynurenine pathway in tryptophan metabolism and decreasing the level of intracellular kynurenine (Kyn). As an endogenous ligand of aryl hydrocarbon receptor, Kyn regulated the expression of cystathionine-γ-lyase (CTH). Notably, in asthma models, enhancing either IDO1 or HS relieved asthma, while inhibiting the activity of CTH exacerbated it. IDO1-Kyn-CTH pathway could be a potential target for treatment for allergic asthma.
先前的研究表明，色氨酸代谢对过敏性炎症至关重要，而吲哚胺2,3-双加氧酶1（IDO1）作为一种关键酶，以其免疫抑制特性而闻名。因此，我们旨在探讨色氨酸代谢，尤其是IDO1，是否影响过敏性哮喘并阐明具体机制。通过临床数据分析、细胞实验探索以及在屋尘螨诱导的哮喘小鼠模型中进行验证，我们最终发现，在过敏性哮喘中，低水平的T1细胞因子与高水平的T2细胞因子共同抑制气道上皮中IDO1的表达，阻碍色氨酸代谢中的犬尿氨酸途径并降低细胞内犬尿氨酸（Kyn）水平。作为芳烃受体的内源性配体，Kyn调节胱硫醚-γ-裂解酶（CTH）的表达。值得注意的是，在哮喘模型中，增强IDO1或HS均可缓解哮喘，而抑制CTH的活性则会加剧哮喘。IDO1-Kyn-CTH途径可能是过敏性哮喘治疗的潜在靶点。
