P2rx1 deficiency alleviates acetaminophen-induced acute liver failure by regulating the STING signaling pathway
Aims Purinergic signaling-mediated mitochondria dysfunction and innate immune-mediated inflammation act as triggers during acetaminophen (APAP)-induced liver injury (AILI). However, the underlying mechanisms by which purinoceptor regulates mitochondria function and inflammation response in the progr...
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Veröffentlicht in: | Cell biology and toxicology 2023-12, Vol.39 (6), p.2761-2774 |
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Hauptverfasser: | , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Aims
Purinergic signaling-mediated mitochondria dysfunction and innate immune-mediated inflammation act as triggers during acetaminophen (APAP)-induced liver injury (AILI). However, the underlying mechanisms by which purinoceptor regulates mitochondria function and inflammation response in the progression of AILI remains unclear.
Methods
First, the hepatic level of purinergic receptor P2X 1 (P2RX1) was identified in the DILI patients and APAP-induced WT mice.
P2rx1
knockout (KO) mice (
P2rx1
−/−
) with 300 mg/kg APAP challenge were used for the analysis of the potential role of P2RX1 in the progression of AILI. Administration of DMX, the activator of stimulator of interferon genes (STING), was performed to investigate the effects of the STING-related pathway on APAP-treated
P2rx1
−/−
mice.
Results
The elevated hepatic P2RX1 levels were found in DILI patients and the AILI mice.
P2rx1
depletion offered protection against the initial stages of AILI, mainly by inhibiting cell death and promoting inflammation resolution, which was associated with alleviating mitochondria dysfunction. Mechanistically,
P2rx1
depletion could inhibit STING-TANK-binding kinase 1 (TBK1)-P65 signaling pathways in vivo. We then showed that DMX-mediated STING activation could greatly aggravate the liver injury of
P2rx1
−/−
mice treated with APAP.
Conclusion
Our data confirmed that P2RX1 was inducted during AILI, identified P2RX1 as a novel regulator in mitochondria dysfunction and STING pathways, and suggested a promising therapeutic approach for AILI involving the blockade of P2RX1.
Graphical abstract
1. It first demonstrated the protective effects of
P2rx1
deficiency on acetaminophen-induced liver injury (AILI).
2.
P2rx1
knockout alleviates mitochondria function and promotes inflammation resolution after APAP treatment.
3. It first reported the regulation of P2RX1 on the STING signaling pathway in the progress of AILI.
4. P2RX1 blockade is a promising therapeutic strategy for AILI. |
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ISSN: | 0742-2091 1573-6822 1573-6822 |
DOI: | 10.1007/s10565-023-09800-1 |