2. Academic Validation
  3. UDPG/P2Y14-STAT1 axis mediates LPS-induced reactive astrogliosis

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

  • Neuropharmacology. 2025 Oct 14:110723. doi: 10.1016/j.neuropharm.2025.110723.
Meng-Yao Wang 1,  Yuan-Hong Deng 1,  Xiao-Feng Ran 1,  Yang Peng 2,  Wen-Jing Ren 1,  Si-Si Lin 1,  Patrizia Rubini 3,  Peter Illes 4,  Yong Tang 5
Affiliations

Affiliations

  • 1 International Joint Research Centre on Purinergic Signalling/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
  • 2 School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
  • 3 International Joint Research Centre on Purinergic Signalling/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Tianfu Jincheng Laboratory, Chengdu 610093, China. Electronic address: patriziarubini@cdutcm.edu.cn.
  • 4 International Joint Research Centre on Purinergic Signalling/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, Leipzig 04107, Germany; Tianfu Jincheng Laboratory, Chengdu 610093, China. Electronic address: peter.illes@medizin.uni-leipzig.de.
  • 5 International Joint Research Centre on Purinergic Signalling/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Tianfu Jincheng Laboratory, Chengdu 610093, China. Electronic address: tangyong@cdutcm.edu.cn.
PMID: 41101520 DOI: 10.1016/j.neuropharm.2025.110723
Abstract

Astrocytes play a vital role in neuroinflammatory processes within the central nervous system (CNS). Increasing evidence suggests that purinergic G protein-coupled receptor P2Y14 is associated with neuroinflammation. However, the expression, distribution, and function of P2Y14 in astrocytes remain unclear. This study aimed to investigate the expression of P2Y14 receptors in astrocytes and their regulatory role in astrocytic inflammatory responses. P2Y14 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 P2Y14 expression in astrocytes. The antagonist of P2Y14 receptor, 4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl2-naphthoic acid (PPTN) reduced glial fibrillary acidic protein (GFAP) expression, while the agonist of P2Y14 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 P2Y14 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 P2Y14 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 P2Y14 expression. This study confirmed that astrocytes express functional P2Y14 receptors and demonstrated their key role in regulating astrocyte activation and inflammatory responses. This regulation may be achieved through the UDPG/P2Y14-STAT1 signaling axis, which provides a new molecular basis for understanding the regulatory mechanisms of astrocytic inflammatory responses.

Keywords

P2Y(14) receptor; interleukin-6; lipopolysaccharide; reactive astrogliosis; signal transducer and activator of transcription 1.

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