UDP-glucose sensing P2Y14R: A novel target for inflammation

Uridine 5'-diphosphoglucose (UDP-G) as a preferential agonist, but also other UDP-sugars, such as UDP galactose, function as extracellular signaling molecules under conditions of cell injury and apoptosis. Consequently, UDP-G is regarded to function as a damage-associated molecular pattern (DAMP), regulating immune responses. UDP-G promotes neutrophil recruitment, leading to the release of pro-inflammatory chemokines. As a potent endogenous agonist with the highest affinity for the P2Y₁₄ receptor (R), it accomplishes an exclusive relationship between P2Y₁₄Rs in regulating inflammation via cyclic adenosine monophosphate (cAMP), nod-like receptor protein 3 (NLRP3) inflammasome, mitogen-activated protein kinases (MAPKs), and signal transducer and activator of transcription 1 (STAT1) pathways. In this review, we initially present a brief introduction into the expression and function of P2Y₁₄Rs in combination with UDP-G. Subsequently, we summarize emerging roles of UDP-G/P2Y₁₄R signaling pathways that modulate inflammatory responses in diverse systems, and discuss the underlying mechanisms of P2Y₁₄R activation in inflammation-related diseases. Moreover, we also refer to the applications as well as effects of novel agonists/antagonists of P2Y₁₄Rs in inflammatory conditions. In conclusion, due to the role of the P2Y₁₄R in the immune system and inflammatory pathways, it may represent a novel target for anti-inflammatory therapy.