title: Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory mucosa.
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.
authors.affiliation: Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905;
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hara
authors.forename: Koji
authors.initials: K
authors.lastname: Iijima
authors.forename: Martha K
authors.initials: MK
authors.lastname: Elias
authors.forename: Satoshi
authors.initials: S
authors.lastname: Seno
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tojima
authors.forename: Takao
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Gail M
authors.initials: GM
authors.lastname: Kephart
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kurabayashi
authors.forename: Hirohito
authors.initials: H
authors.lastname: Kita
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001963:Bromelains / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010206:Papain / Q000276:immunology / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000276:immunology* / Q000494:pharmacology; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D014527:Uric Acid / Q000276:immunology* / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000485:Allergens; D016207:Cytokines; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D014527:Uric Acid; D001963:Bromelains; D010447:Peptide Hydrolases; D010206:Papain; D000094632:Thymic Stromal Lymphopoietin