Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps.

Abstract

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.

• Authors: 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
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 141 Issue 2 Pg. 586-600.e6 (02 2018) ISSN: 1097-6825 [Electronic] United States
• PMID: 28689792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• AHR protein, human
• Ahr protein, mouse
• Basic Helix-Loop-Helix Transcription Factors
• IDO1 protein, human
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Receptors, Aryl Hydrocarbon
• Receptors, Glutamate
• kynurenine receptor
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, immunology)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics, immunology)
• Chronic Disease
• Eosinophils (immunology, pathology)
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (genetics, immunology)
• Mast Cells (immunology, pathology)
• Mice
• Mice, Knockout
• Nasal Polyps (genetics, immunology, pathology)
• Receptors, Aryl Hydrocarbon (genetics, immunology)
• Receptors, Glutamate (genetics, immunology)
• Rhinitis (genetics, immunology, pathology)
• Signal Transduction (genetics, immunology)
• Sinusitis (genetics, immunology, pathology)