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

J Clin Invest. 2021 Apr 1;131(7):e140709. doi: 10.1172/JCI140709.


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.

Keywords: Asthma; Inflammation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Allergens / immunology
  • Animals
  • Asthma / genetics
  • Asthma / immunology*
  • Asthma / pathology
  • Chemokine CCL24 / genetics
  • Chemokine CCL24 / immunology
  • Eosinophils / immunology*
  • Eosinophils / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Pulmonary Eosinophilia / genetics
  • Pulmonary Eosinophilia / immunology*
  • Pulmonary Eosinophilia / pathology
  • Receptors, Purinergic P2Y / deficiency
  • Receptors, Purinergic P2Y / immunology*
  • Th2 Cells / immunology
  • Th2 Cells / pathology
  • Uridine Diphosphate Glucose / genetics
  • Uridine Diphosphate Glucose / immunology*


  • Allergens
  • Ccl24 protein, mouse
  • Chemokine CCL24
  • P2ry14 protein, mouse
  • Receptors, Purinergic P2Y
  • Uridine Diphosphate Glucose