Uridine diphosphate-glucose/P2Y14R axis is a nonchemokine pathway that selectively promotes eosinophil accumulation

Abstract

Allergic asthma is a chronic inflammatory airway disease characterized by dysregulated type 2 immune responses, including degranulating airway eosinophils that induce tissue damage and airway hyperresponsiveness (AHR). The type 2 cytokines interleukin 5 (IL-5) and IL-13 and the eosinophil-specific chemokine CCL11/CCL24/CCL26 axis recruit, activate, and regulate eosinophils in the airways. In this issue of the JCI, Karcz et al. identified a mechanism involving the nucleotide sugar UDP-glucose (UDP-G) and the purinergic receptor P2Y14R in amplifying eosinophil accumulation in the lung. During type 2 inflammation, UDP-G activates P2Y14R on eosinophils, inducing the cells to move and migrate into the lung. Pharmacologically or genetically inhibiting P2Y14R on eosinophils attenuated eosinophil infiltration and AHR. Future experiments, including identifying additional type 2 factors regulating P2Y14R expression on lung eosinophils, are necessary to ascertain the impact of targeting P2Y14R as an alternative or adjunctive therapy to current type 2 biologics for the treatment of asthma.

Figure 1. The uridine diphosphate–glucose (UDP-G)/P2Y₁₄R axis selectively regulates eosinophil migration by promoting chemokinesis and amplifying chemotaxis.

In response to allergen challenge, group-2 innate lymphoid cells (ILC2s) and CD4⁺ T helper type 2 lymphocytes (Th2 cells) expand and secrete interleukin 5 (IL-5) and IL-13, promoting allergic inflammation. IL-5 promotes eosinophil differentiation, expansion in the bone marrow, and egress into the circulation. In the lung, IL-13 promotes the local production of eosinophil-specific chemokines CCL11, CCL24, and CCL26, which signal through CCR3 to promote chemotaxis and eosinophil migration to the airways. This IL-5/IL-13/CCR3 axis is the primary mechanism, in conjunction with vascular adhesion molecules, for recruiting eosinophils into the lung during type 2 inflammation. UDP-G accumulation in the lung following allergen provocation signals through P2Y₁₄R to induce eosinophil chemokinesis and amplify chemokine-directed eosinophil migration and accumulation in the lung. Loss of the UDP-G/P2Y₁₄R signaling in P2ry14^–/– eosinophils diminishes CCR3-mediated eosinophil chemokinesis and eosinophil accumulation in the lung and induction of the asthma manifestations.