Airway Uric Acid Is a Sensor of Inhaled Protease Allergens and Initiates Type 2 Immune Responses in Respiratory Mucosa

Abstract

While type 2 immune responses to environmental antigens 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. Here we report that IL-33 and thymic stromal lymphopoietin (TSLP) were produced quickly in the lungs of naïve mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and TSLP sensitized naïve animals to an innocuous airway antigen OVA, which resulted in production of type 2 cytokines and IgE antibody and eosinophilic airway inflammation when mice were challenged with the same antigen. 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 naïve 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.

Group 2 Innate Lymphoid Cells Promote an Early Antibody Response to a Respiratory Antigen in Mice

“…Thus, we took a similar approach to induce NP-Ficoll-specific Ig responses by exposing mice intranasally (i.n.) to NP-Ficoll together with a cysteine protease, bromelain, as an adjuvant (22). We isolated lung ILC2s from non-sensitized WT C57BL/6 mice that had been injected i.p.…”

Comprehensive metabolomics identifies the alarmin uric acid as a critical signal for the induction of peanut allergy

“…These findings are not restricted to the use of CT since similar preventionreconstitution of this phenotype was observed in a model of skin sensitization where tissue damage was caused by tapestripping. Evidence for the role of UA (18,19), IL-33 (8,20), ATP (21), and HMGB1 (22) in allergic airway inflammation, food allergy, and allergic rhinitis argue for the critical importance of tissue damage and the pervasive role of alarmins in the initiation of allergic sensitization and, ultimately, Th2 immunity. In a model of oral sensitization, such as the one used here, we have shown that IL-33 plays a similarly critical role (8) and, more recently, we have demonstrated that eosinophils and, specifically, eosinophil peroxidase (EPO) are essential for the development of peanut allergy (13).…”

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells

“…RAGE is highly expressed on type I alveolar epithelial cells (41–43), while IL-33 localizes to nuclei and is released by type II alveolar epithelial cells in response to damage (49–51). How RAGE activation might direct increased IL-33 expression is unclear, but it is known that type I and type II alveolar epithelial cells communicate through multiple paracrine and juxtacrine signaling pathways (52–55). Future studies will elucidate how these pathways propagate upstream inputs from RAGE.…”