Distinct TLR-mediated pathways regulate house dust mite–induced allergic disease in the upper and lower airways

doi:10.1016/j.jaci.2012.07.050

Journal of Allergy and Clinical Immunology

Volume 131, Issue 2, February 2013, Pages 549-561

https://doi.org/10.1016/j.jaci.2012.07.050 Get rights and content

Background

Allergic rhinitis (AR) and asthma are 2 entities of allergic airway diseases that frequently occur together, which is referred to as united airways. In contrast to this general concept, we hypothesized that innate immunity of the upper and lower airways is respectively distinctive, because the immunologic conditions of the nasal and lung mucosa as well as the functions of the immune cells within their epithelia are different.

Objective

We wanted to identify distinctive mechanisms of innate immunity in the nose and lung mucosa, which are responsible for house dust mite (HDM)–induced AR and allergic asthma (AA), respectively.

Methods

We constructed a mouse model of AR or AA induced by sensitization and consequent provocation with HDM extracts.

Results

HDM-derived β-glucans, rather than LPS, were proven to be essential to activating innate immunity in the nasal mucosa and triggering AR, which depended on Toll-like receptor 2 (TLR2), but not on TLR4; however, the LPS/TLR4 signaling axis, rather than β-glucans/TLR2, was critical to HDM-induced AA. These differences were attributed to the specific role of β-glucans and LPS in inducing the surface expression of TLR2 and TLR4 and their translocation to lipid rafts in nasal and bronchial epithelial cells, respectively. We also showed that dual oxidase 2–generated reactive oxygen species mediate both β-glucan–induced TLR2 activation and LPS-induced TLR4 activation.

Conclusions

We describe a novel finding of distinctive innate immunity of the nose and lungs, respectively, which trigger AR and AA, by showing the critical role of HDM-induced TLR activation via dual oxidase 2–mediated reactive oxygen species.

Section snippets

Methods

For details on methods, see this article's Methods section (in the Online Repository available at www.jacionline.org).

β-Glucans and LPS within HDM-triggered innate immunity in the upper and lower airways, respectively

Because β-glucans and LPS are known to be the main PAMPs within HDM extracts that activate innate immunity in the airway epithelium,13, 17, 19, 22 we examined their roles in the HDM-induced innate immune responses in airway epithelial cells. We pretreated HDM extracts with either β-glucanase to degrade β-glucan structures (HDMΔβ-glucan) or polymyxin B to inactivate LPS (HDMΔLPS) before treating primary normal human nasal epithelial (NHNE) cells. First, we measured the level of CCL20 secretion

Discussion

Here, we clearly showed that HDM-derived β-glucans and TLR2 were critical for activating innate immunity in the nasal mucosa and subsequent AR by showing that CCL20 secretion, DC recruitment, and HDM-induced AR were attenuated in HDMΔβ-glucan challenge or TLR2^−/− mice. In contrast, LPS/TLR4 signaling axis, rather than β-glucan/TLR2, played a pivotal role in activating innate immunity in the lung mucosa and resultant AA in our study, in agreement with previous studies that TLR4, rather than

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: Supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (grant 2012-0000803 to J.-H.Y. and grant 2010-0022899 to J.-H.R.) and by the Yonsei University College of Medicine (grant 6-2009-0115 to J.-H.R.). None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

: Disclosure of potential conflict of interest: J.-H. Ryu has received grants from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology and Yonsei University College of Medicine. J.-H. Yoon has received grants from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology. The rest of the authors declare that they have no relevant conflicts of interest.

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Mechanisms of allergy and clinical immunologyDistinct TLR-mediated pathways regulate house dust mite–induced allergic disease in the upper and lower airways

Background

Objective

Methods

Results

Conclusions

Section snippets

Methods

β-Glucans and LPS within HDM-triggered innate immunity in the upper and lower airways, respectively

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Mucosal Immunol

Trends Immunol

Trends Immunol

J Allergy Clin Immunol

Am J Otolaryngol

Blood

J Surg Res

FEBS Lett

Free Radic Biol Med

J Biol Chem

Impact of allergic rhinitis on asthma: effects on bronchial hyperreactivity

Allergy

The connection between allergic rhinitis and bronchial asthma

Curr Opin Pulm Med

United airways concept: what does it teach us about systemic inflammation in airways disease?

Proc Am Thorac Soc

Analysis of the lung microbiome in the “healthy” smoker and in COPD

PLoS One

Bacterial competition for human nasal cavity colonization: role of Staphylococcal agr alleles

Appl Environ Microbiol

Immunological functions of the pulmonary epithelium

Eur Respir J

Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: a comparison between upper and lower airways

Clin Exp Allergy

Comparison between nasal and bronchial inflammation in asthmatic and control subjects

Am J Respir Crit Care Med

Modification of allergic inflammation in murine model of rhinitis by different bacterial ligands: involvement of mast cells and dendritic cells

Clin Exp Allergy

United airways: circulating Th2 effector cells in an allergic rhinitis model are responsible for promoting lower airways inflammation

Clin Exp Allergy

Mechanisms of allergy and clinical immunology
Distinct TLR-mediated pathways regulate house dust mite–induced allergic disease in the upper and lower airways