UDP-glucose and P2Y(14) receptor amplify allergen-induced airway eosinophilia
| Autor: | Leesa J. Deterding, Sara A. Grimm, Donald N. Cook, Jason Williams, Gregory S. Whitehead, Tadeusz P Karcz, Keiko Nakano, Hideki Nakano, Kenneth A. Jacobson |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Uridine Diphosphate Glucose Inflammation Allergic sensitization 03 medical and health sciences 0302 clinical medicine Medicine Eosinophilia Humans Asthma Interleukin-13 business.industry General Medicine Eosinophil respiratory system medicine.disease respiratory tract diseases Eosinophils 030104 developmental biology medicine.anatomical_structure Glucose 030220 oncology & carcinogenesis Immunology medicine.symptom business Airway CCL24 Glucocorticoid medicine.drug Research Article |
| Zdroj: | J Clin Invest |
| Popis: | Airway eosinophilia is a hallmark of allergic asthma and is associated with mucus production, airway hyperresponsiveness, and shortness of breath. Although glucocorticoids are widely used to treat asthma, their prolonged use is associated with several side effects. Furthermore, many individuals with eosinophilic asthma are resistant to glucocorticoid treatment, and they have an unmet need for novel therapies. Here, we show that UDP-glucose (UDP-G), a nucleotide sugar, is selectively released into the airways of allergen-sensitized mice upon their subsequent challenge with that same allergen. Mice lacking P2Y(14)R, the receptor for UDP-G, had decreased airway eosinophilia and airway hyperresponsiveness compared with wild-type mice in a protease-mediated model of asthma. P2Y(14)R was dispensable for allergic sensitization and for the production of type 2 cytokines in the lung after challenge. However, UDP-G increased chemokinesis in eosinophils and enhanced their response to the eosinophil chemoattractant, CCL24. In turn, eosinophils triggered the release of UDP-G into the airway, thereby amplifying eosinophilic recruitment. This positive feedback loop was sensitive to therapeutic intervention, as a small molecule antagonist of P2Y(14)R inhibited airway eosinophilia. These findings thus reveal a pathway that can be therapeutically targeted to treat asthma exacerbations and glucocorticoid-resistant forms of this disease. |
| Databáze: | OpenAIRE |
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