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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

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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 5

UDP-glucose amplifies eosinophil recruitment to the airway.

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UDP-glucose amplifies eosinophil recruitment to the airway.
(A) Mass spe...
(A) Mass spectrometry measurements of UDP-hexoses in BALF 8 hours after OVA challenge of mice previously sensitized using ASP/OVA or LPS/OVA. Data represent sample readouts relative to the internal standard (ITSD), 13C6-UDP-glucose (included in the fluid used for lavage). (B and C) Time course for airway levels of UDP-hexoses (B), and for eosinophil numbers in the indicated locations (C). Analyses were performed on C57BL/6J mice sensitized twice with OVA/ASP, challenged once with OVA, and harvested at the indicated times. Data shown represent means ± SEM (n = 3–5) from a single experiment. (D) Air space, blood, and marginated eosinophils in ASP/OVA-sensitized mice at 16 hours after OVA challenge. (E) Airway levels of CCL11 and CCL24 in ASP/OVA-sensitized mice, 4 hours after OVA challenge. (F) MFI of CCR3 on lung eosinophils. (G) Schematic representation of in vitro cell migration assay. (H) Migration of WT and P2ry14–/– eosinophils in response to the indicated agents added to the top and/or bottom chambers. U, UDP-glucose. (I) UDP-hexose levels in BALF after adoptive transfer of the indicated cells into the airways. (J) Effect of anti-CCR3 antibody on lung eosinophils. (K) Effect of anti-CCR3 antibody on UDP-hexoses in BALF. IC, isotype control antibody. Data shown represent mean values ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****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.

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