UDPG/P2Y14-STAT1 axis mediates LPS-induced reactive astrogliosis

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Astrocytes play a vital role in neuroinflammatory processes within the central nervous system (CNS). Increasing evidence suggests that purinergic G protein-coupled receptor P2Y 14 is associated with neuroinflammation. However, the expression, distribution, and function of P2Y 14 in astrocytes remain unclear. This study aimed to investigate the expression of P2Y 14 receptors in astrocytes and their regulatory role in astrocytic inflammatory responses. P2Y 14 expression was confirmed in primary astrocytes isolated from the mouse cerebral cortex using immunofluorescence techniques. Western blot and RT-qPCR analyses showed that lipopolysaccharide (LPS) stimulation significantly increased P2Y 14 expression in astrocytes. The antagonist of P2Y 14 receptor, 4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl2-naphthoic acid (PPTN) reduced glial fibrillary acidic protein (GFAP) expression, while the agonist of P2Y 14 receptor, uridine diphosphate glucose (UDPG) promoted it in astrocytes. Mechanistically, PPTN inhibited the expression of signal transducer and activator of transcription 1 (STAT1) and its phosphorylated form (p-STAT1), while UDPG enhanced the activation of STAT1/p-STAT1. Treatment with the P2Y 14 antagonist PPTN resulted in significant inhibition of interleukin (IL)-6, IL-18, and tumor necrosis factor-alpha (TNF-α) release. By contrast, stimulation of the P2Y 14 receptor with its agonist UDPG induced a substantial increase in the levels of these inflammatory mediators. These results were further validated in the cell line of mouse astrocyte C8-D1A using pharmacological approaches and lentiviral transduction to modulate P2Y 14 expression. This study confirmed that astrocytes express functional P2Y 14 receptors and demonstrated their key role in regulating astrocyte activation and inflammatory responses. This regulation may be achieved through the UDPG/P2Y 14 -STAT1 signaling axis, which provides a new molecular basis for understanding the regulatory mechanisms of astrocytic inflammatory responses. • P2Y 14 is functionally expressed in astrocytes • Lipopolysaccharide induces increased expression of P2Y 14 in astrocytes • Pharmacological inhibition or knockdown of P2Y 14 attenuates LPS-induced inflammatory responses in astrocytes • P2Y 14 -STAT1 axis regulates astrocytic inflammatory responses

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