P2Y14 receptor activation and neutrophil signaling: linking inflammation to systemic pathophysiology

Neutrophils are essential effector cells of the innate immune system, acting as the first line of defense against infection and tissue injury. Among the purinergic receptors expressed in these cells, P2Y14 has gained increasing attention in recent years for its role in modulating neutrophil recruitment and activation in inflammatory contexts. This receptor is activated mainly by uridine diphosphoglucose (UDP-glucose) and other UDP-sugars released during cellular stress or damage. Through the activation of G protein-coupled pathways, particularly via Gi/o and RhoA signaling, P2Y14 influences key neutrophil functions, including chemotaxis, cytoskeletal rearrangements, and oxidative responses. Despite its pro-inflammatory potential, and the increasing amount of literature data in recent years, P2Y14's complete physiological and pathological roles remain underexplored. Literature data also highlight its involvement in diseases like glioblastoma and COVID-19, where, due to increased neutrophil infiltration, it exacerbates inflammation, tissue damage, and stress. Therefore, targeting P2Y14 may be a promising strategy to modulate neutrophil chemotaxis and mitigate unwanted harmful inflammatory responses. This review discusses the characteristics and signaling mechanisms of P2Y14 in neutrophils, as well as the relevant implications of this pathway for neutrophil function.