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

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

doi:10.1016/j.jaci.2017.06.013

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

J Allergy Clin Immunol. 2018 Feb;141(2):586-600.e6. doi: 10.1016/j.jaci.2017.06.013. Epub 2017 Jul 6.

Authors

Heng Wang¹, Danh C Do², Jinxin Liu³, Baofeng Wang³, Jingjing Qu⁴, Xia Ke², Xiaoyan Luo², Ho Man Tang⁵, Ho Lam Tang⁶, Chengping Hu⁷, Mark E Anderson⁸, Zheng Liu⁹, Peisong Gao¹⁰

Affiliations

¹ 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.
² Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md.
³ Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ 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.
⁵ Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, Md.
⁶ Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md.
⁷ Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
⁸ Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Md.
⁹ Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: zhengliuent@hotmail.com.
¹⁰ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md. Electronic address: pgao1@jhmi.edu.

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.

Keywords: Chronic rhinosinusitis with nasal polyps; aryl hydrocarbon receptor (AhR); calmodulin-dependent protein kinase II (CaMKII); kynurenine; mast cell.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding