Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory Mucosa

Kenichiro Hara, Koji Iijima, Martha K. Elias, Satoshi Seno, Ichiro Tojima, Takao Kobayashi, Gail M. Kephart, Masahiko Kurabayashi, Hirohito Kita

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Although type 2 immune responses to environmental Ags are thought to play pivotal roles in asthma and allergic airway diseases, the immunological mechanisms that initiate the responses are largely unknown. Many allergens have biologic activities, including enzymatic activities and abilities to engage innate pattern-recognition receptors such as TLR4. In this article, we report that IL-33 and thymic stromal lymphopoietin were produced quickly in the lungs of naive mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and thymic stromal lymphopoietin sensitized naive animals to an innocuous airway Ag OVA, which resulted in production of type 2 cytokines and IgE Ab, and eosinophilic airway inflammation when mice were challenged with the same Ag. Importantly, upon exposure to proteases, uric acid (UA) was rapidly released into the airway lumen, and removal of this endogenous UA by uricase prevented type 2 immune responses. UA promoted secretion of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of naive animals induced extracellular release of IL-33, followed by both innate and adaptive type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated asthma phenotypes that were caused by repeated exposure to natural airborne allergens. These findings provide mechanistic insights into the development of type 2 immunity to airborne allergens and recognize airway UA as a key player that regulates the process in respiratory mucosa. The Journal of Immunology, 2014, 192: 4032-4042.

Original languageEnglish (US)
Pages (from-to)4032-4042
Number of pages11
JournalJournal of Immunology
Volume192
Issue number9
DOIs
StatePublished - May 1 2014

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Respiratory Mucosa
Uric Acid
Allergens
Peptide Hydrolases
Asthma
Urate Oxidase
Bromelains
Pattern Recognition Receptors
Papain
Cysteine Proteases
Immune System Diseases
Adaptive Immunity
Allergy and Immunology
Immunoglobulin E
Immunity
Epithelial Cells
Cytokines
Inflammation
Phenotype
Lung

ASJC Scopus subject areas

  • Immunology

Cite this

Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory Mucosa. / Hara, Kenichiro; Iijima, Koji; Elias, Martha K.; Seno, Satoshi; Tojima, Ichiro; Kobayashi, Takao; Kephart, Gail M.; Kurabayashi, Masahiko; Kita, Hirohito.

In: Journal of Immunology, Vol. 192, No. 9, 01.05.2014, p. 4032-4042.

Research output: Contribution to journalArticle

Hara, K, Iijima, K, Elias, MK, Seno, S, Tojima, I, Kobayashi, T, Kephart, GM, Kurabayashi, M & Kita, H 2014, 'Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory Mucosa', Journal of Immunology, vol. 192, no. 9, pp. 4032-4042. https://doi.org/10.4049/jimmunol.1400110
Hara, Kenichiro ; Iijima, Koji ; Elias, Martha K. ; Seno, Satoshi ; Tojima, Ichiro ; Kobayashi, Takao ; Kephart, Gail M. ; Kurabayashi, Masahiko ; Kita, Hirohito. / Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory Mucosa. In: Journal of Immunology. 2014 ; Vol. 192, No. 9. pp. 4032-4042.
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