Functional Role of Kynurenine and Aryl hydrocarbon Receptor Axis in Chronic Rhinosinusitis with Nasal Polyps

Publication date: Available online 6 July 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Heng Wang, Danh C. Do, Jinxin Liu, Baofeng Wang, Jingjing Qu, Xia Ke, Xiaoyan Luo, Ho Man Tang, Ho Lam Tang, Chengping Hu, Mark E. Anderson, Zheng Liu, Peisong Gao
BackgroundChronic 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).ObjectivesDetermine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP.MethodsWe measured expression of indoleamine 2, 3-dioxygenase 1 (IDO1), tryptophan 2, 3-dioxygenase (TDO2), KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls. KYN-potentiated ovalbumin (OVA)-induced reactive oxygen species (ROS) generation, cell activation, and ox-CaMKII expression were investigated in wild type (WT) and AhR deficient (AhR^-/-) mast cells. The role of ox-CaMKII in mast cell activation was further investigated.ResultsNasal polyps in CRSwNP showed an increased expression of IDO1, TDO2, 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 non-eosinophilic polyps and controls. Furthermore, KYN potentiated OVA-induced ROS generation, intracellular Ca²⁺ levels, cell activation, and expression of ox-CaMKII in WT, but not in AhR^-/- mast cells. Compared with non-eosinophilic polyps and controls, eosinophilic polyps showed increased expression of ox-CaMKII in mast cells. Mast cells from ROS-resistant CaMKII MMVVδ mice or pre-treated with CaMKII inhibitor showed protection against KYN-promoted OVA-induced mast cell activation.ConclusionThese 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.

Teaser

The pathogenesis of chronic rhinosinusitis with nasal polyps is associated with increased levels of kynurenine, a tryptophan metabolite, which potentiated allergen-induced mast cell activation through the aryl hydrocarbon receptor and Calmodulin-dependent protein kinase II.


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