UDP-glucose and P2Y14 receptor amplify allergen-induced airway eosinophilia
Tadeusz P. Karcz, … , Kenneth A. Jacobson, Donald N. Cook
Tadeusz P. Karcz, … , Kenneth A. Jacobson, Donald N. Cook
Published April 1, 2021
Citation Information: J Clin Invest. 2021;131(7):e140709. https://doi.org/10.1172/JCI140709.
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Research Article Inflammation

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

Abstract

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.

Authors

Tadeusz P. Karcz, Gregory S. Whitehead, Keiko Nakano, Hideki Nakano, Sara A. Grimm, Jason G. Williams, Leesa J. Deterding, Kenneth A. Jacobson, Donald N. Cook

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Figure 1

P2ry14 is required for airway eosinophilia and AHR in protease-mediated models of asthma.

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P2ry14 is required for airway eosinophilia and AHR in protease-mediated...
(A) Timeline showing allergic sensitization, challenge, and harvest of C57BL/6J wild-type and genetically matched P2ry14–/– (KO) mice in LPS- and protease-mediated (ASP and PAP) models of asthma. (B) Airway inflammation at 48 hours after allergen challenge in wild-type mice (gray rectangles) and P2ry14–/– mice (white rectangles) previously sensitized using the indicated adjuvant. Shown are mean values ± SEM (n = 12–17 per group, except for nontreated or OVA-only-treated groups, where n = 3). (C) Airway resistance (R) measurements in OVA-challenged mice previously sensitized using OVA only, ASP/OVA, or LPS/OVA. Mean (± SEM) values are shown (n = 10) for baseline (B) and after administration of the indicated doses of methacholine. Results shown are from a single experiment, representative of 2. ND, not detectable. *P < 0.05; **P < 0.01; ****P < 0.0001; NS, not significant; analyzed using 1-way ANOVA followed by Bonferroni’s post hoc test. (D) Concentrations of IL-5 and IL-13 in BALF after OVA challenge in ASP/OVA asthma model. (E) Concentrations of OVA-specific IgE in serum. Means ± SEM are shown for naive mice, and for OVA with and without ASP-sensitized and OVA-challenged animals. (F) Representative Alcian blue– and periodic acid–Schiff–stained sections showing mucus-producing cells. Sections were prepared from lungs of C57BL/6J wild-type and genetically matched P2ry14–/– mice (left). Scale bar: 200 μm. Also shown are compiled data for mean numbers ± SEM of mucus-producing cells in individual lung slices from the indicated groups.