UDP-glucose and P2Y14 receptor amplify allergen-induced airway eosinophilia
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
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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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 4

Expression of P2ry14 in lung eosinophils is essential for eosinophilic airway inflammation.

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Expression of P2ry14 in lung eosinophils is essential for eosinophilic a...
(A) Cell numbers for the indicated leukocyte types in airways of reciprocal bone marrow–chimeric (BM-chimeric) mice generated using WT and P2ry14–/– animals and subjected to the ASP/OVA model of asthma. (B and C) Expression of P2ry14 in the indicated populations of leukocytes and stromal cells from lungs of C57BL/6J mice (B), and in eosinophils during their maturation and migration to the periphery (C). (D) Generation of mixed BM chimeras by injecting equal numbers of BM cells from WT (CD45.1+) and P2ry14-null (CD45.2+) mice into irradiated Cd45.1/Cd45.2 heterozygous recipients. Dot-plot cytograms show representative flow cytometry results for CD45.1 and CD45.2 staining of BM (left) and lung cells (right) of nonchallenged mice, indicating similar reconstitution of leukocyte populations of each donor genotype. (E) Ratio of wild-type (CD45.1+) to P2ry14–/– (CD45.2+) eosinophils and neutrophils in the BM and lung parenchyma of naive mice, and in the airspace of OVA-challenged mice previously sensitized with ASP/OVA. (F) Allergic airway inflammation in mice with conditional P2ry14 disruption in LyzM-expressing myeloid cells (left), and disruption in Cd11c-expressing alveolar macrophages and dendritic cells (right). (G) Allergic airway inflammation in mice with P2ry14 disruption in eosinophils. Data shown represent mean values ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Data were analyzed using 2-tailed Student’s t test for pairwise comparisons, or 1-way ANOVA followed by Tukey’s post hoc test for multiple comparisons.