Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps,Journal of Allergy and Clinical Immunology

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Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2017-07-06 , DOI: 10.1016/j.jaci.2017.06.013
Heng Wang ₁ , Danh C Do ₂ , Jinxin Liu ₃ , Baofeng Wang ₃ , Jingjing Qu ₄ , Xia Ke ₂ , Xiaoyan Luo ₂ , Ho Man Tang ₅ , Ho Lam Tang ₆ , Chengping Hu ₇ , Mark E Anderson ₈ , Zheng Liu ₃ , Peisong Gao ₂

Affiliation

Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md.
Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, Md.
Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md.
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Md.

Background

Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell–mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR).

Objectives

We sought to determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP.

Methods

We measured the expression of indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase, KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls. KYN-potentiated ovalbumin (OVA)-induced ROS generation, cell activation, and ox-CaMKII expression were investigated in wild-type and AhR-deficient (AhR^−/−) mast cells. The role of ox-CaMKII in mast cell activation was further investigated.

Results

Nasal polyps in CRSwNP showed an increased expression of indoleamine 2,3-dioxygenase 1, tryptophan2,3-dioxygenase, and KYN compared with controls. AhR was predominantly expressed in mast cells in nasal polyps. Activated mast cells and local IgE levels were substantially increased in eosinophilic polyps compared with noneosinophilic polyps and controls. Furthermore, KYN potentiated OVA-induced ROS generation, intracellular Ca²⁺ levels, cell activation, and expression of ox-CaMKII in wild-type, but not in AhR^−/− mast cells. Compared with noneosinophilic polyps and controls, eosinophilic polyps showed increased expression of ox-CaMKII in mast cells. Mast cells from ROS-resistant CaMKII MMVVδ mice or pretreated with CaMKII inhibitor showed protection against KYN-promoted OVA-induced mast cell activation.

Conclusions

These studies support a potentially critical but previously unidentified function of the KYN/AhR axis in regulating IgE-mediated mast cell activation through ROS and ox-CaMKII in CRSwNP.

中文翻译：

犬尿氨酸和芳烃受体轴在慢性鼻窦炎伴鼻息肉中的功能作用

背景

慢性鼻窦炎伴鼻息肉（CRSwNP）与肥大细胞介导的炎症和氧化应激升高有关。犬尿氨酸 (KYN) 是一种内源性色氨酸代谢物，可通过芳基烃受体 (AhR) 促进过敏原诱导的肥大细胞活化。

目标

我们试图确定 KYN/AhR 轴和氧化应激在肥大细胞激活和 CRSwNP 发展中的作用。

方法

我们测量了鼻息肉和对照中吲哚胺 2,3-双加氧酶 1、色氨酸 2,3-双加氧酶、KYN 和氧化钙调蛋白依赖性蛋白激酶 II (ox-CaMKII) 的表达。在野生型和 AhR 缺陷型 (AhR ^−/− ) 肥大细胞中研究了 KYN 强化卵清蛋白 (OVA) 诱导的 ROS 生成、细胞激活和 ox-CaMKII 表达。进一步研究了 ox-CaMKII 在肥大细胞激活中的作用。

结果

与对照组相比，CRSwNP 中的鼻息肉显示吲哚胺 2,3-双加氧酶 1、色氨酸2,3-双加氧酶和 KYN 的表达增加。AhR 主要在鼻息肉的肥大细胞中表达。与非嗜酸性息肉和对照相比，嗜酸性息肉中活化的肥大细胞和局部 IgE 水平显着升高。此外，KYN 增强了 OVA 诱导的 ROS 生成、细胞内 Ca ²⁺水平、细胞活化和野生型中 ox-CaMKII 的表达，但在 AhR ^−/−肥大细胞中则不然。与非嗜酸性息肉和对照相比，嗜酸性息肉显示肥大细胞中 ox-CaMKII 的表达增加。来自 ROS 抗性 CaMKII MMVVδ 小鼠或用 CaMKII 抑制剂预处理的肥大细胞显示出针对 KYN 促进的 OVA 诱导的肥大细胞激活的保护作用。