The Significance of Hypothiocyanite Production via the Pendrin/DUOX/Peroxidase Pathway in the Pathogenesis of Asthma.

Kenji Izuhara,Yasuhiro Nanri,Shoichi Suzuki,Tomohito Yoshihara,Yasutaka Mitamura,Masahiro Ogawa,Satoshi Nunomura

doi:10.1155/2017/1054801

Kenji Izuhara, Yasuhiro Nanri + Show 5 more

Open Access

https://doi.org/10.1155/2017/1054801

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Abstract

Inhaled corticosteroids (ICSs) are used as first-line drugs for asthma, and various novel antiasthma drugs targeting type 2 immune mediators are now under development. However, molecularly targeted drugs are expensive, creating an economic burden on patients. We and others previously found pendrin/SLC26A4 as a downstream molecule of IL-13, a signature type 2 cytokine critical for asthma, and showed its significance in the pathogenesis of asthma using model mice. However, the molecular mechanism of how pendrin causes airway inflammation remained elusive. We have recently demonstrated that hypothiocyanite (OSCN−) produced by the pendrin/DUOX/peroxidase pathway has the potential to cause airway inflammation. Pendrin transports thiocyanate (SCN−) into pulmonary lumens at the apical side. Peroxidases catalyze SCN− and H2O2 generated by DUOX into OSCN−. Low doses of OSCN− activate NF-κB in airway epithelial cells, whereas OSCN− in high doses causes necrosis of the cells, inducing the release of IL-33 and accelerating inflammation. OSCN− production is augmented in asthma model mice and possibly in some asthma patients. Heme peroxidase inhibitors, widely used as antithyroid agents, diminish asthma-like phenotypes in mice, indicating the significance of this pathway. These findings suggest the possibility of repositioning antithyroid agents as antiasthma drugs.

Highlights

Asthma is a common and chronic respiratory disease characterized by variable symptoms and features―wheezing, shortness of breath, cough, and expiratory airflow limitation [1]
To identify a novel mediator involved in asthma pathogenesis downstream of the IL-13 signals, we and others previously used DNA microarray to search for IL-13-induced molecules in human airway epithelial cells, finding that the SLC26A4 gene encoding pendrin is a downstream molecule of IL-13 [7, 20, 21]
We focused on SCN−, because pendrin can transport SCN− into the apical side of airway epithelial cells [22] and OSCN− derived from SCN− plays a critical role in the innate defense of mucosal surfaces [43,44,45]

Summary

Introduction

Asthma is a common and chronic respiratory disease characterized by variable symptoms and features―wheezing, shortness of breath, cough, and expiratory airflow limitation [1]. We investigated how pendrin causes airway inflammation, pinpointing the significance of the hypothiocyanite (OSCN−) production via the pendrin/DUOX/peroxidase pathway [9, 10] These results have revealed for the first time the involvement of anion or its derivative in the pathogenesis of asthma. To identify a novel mediator involved in asthma pathogenesis downstream of the IL-13 signals, we and others previously used DNA microarray to search for IL-13-induced molecules in human airway epithelial cells, finding that the SLC26A4 gene encoding pendrin is a downstream molecule of IL-13 [7, 20, 21]. Since expression of IL-17A is a hallmark of severe asthma correlated with infiltration of neutrophils [35], pendrin may be maximally expressed in severe asthma patients

The Pathological Roles of Pendrin in Asthma

Findings

Conclusion