UDP-glucose and P2Y14 receptor amplify allergen-induced airway eosinophilia

作者：Tadeusz P. Karcz, Gregory S. Whitehead, Keiko Nakano, Hideki Nakano, Sara A. Grimm, Jason Grant Williams, Leesa J. Deterding, Kenneth A. Jacobson, Donald N. Cook · 发表于：Journal of Clinical Investigation · 年份：2021 · DOI：10.1172/jci140709 · 被引用次数：64 · 研究领域：Asthma and respiratory diseases、Receptor Mechanisms and Signaling、Adenosine and Purinergic Signaling

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 P2Y14R, the receptor for UDP-G, had decreased airway eosinophilia and airway hyperresponsiveness compared with wild-type mice in a protease-mediated model of asthma. P2Y14R 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 P2Y14R 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.