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.

中文翻译：

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P2rx1 缺陷通过调节 STING 信号通路减轻对乙酰氨基酚诱导的急性肝衰竭

宗旨

嘌呤能信号介导的线粒体功能障碍和先天免疫介导的炎症在对乙酰氨基酚 (APAP) 诱导的肝损伤 (AILI) 期间充当触发器。然而，嘌呤受体在 AILI 进展中调节线粒体功能和炎症反应的潜在机制仍不清楚。

方法

首先，在 DILI 患者和 APAP 诱导的 WT 小鼠中鉴定了嘌呤能受体 P2X 1 (P2RX1) 的肝脏水平。具有 300 mg/kg APAP 攻击的P2rx1敲除 (KO) 小鼠 ( P2rx1 ^-/- ) 用于分析 P2RX1 在 AILI 进展中的潜在作用。施用 DMX（干扰素基因刺激物 (STING) 的激活剂）以研究 STING 相关通路对 APAP 处理的P2rx1 ^-/-小鼠的影响。

结果

在 DILI 患者和 AILI 小鼠中发现肝脏 P2RX1 水平升高。P2rx1耗竭提供了针对 AILI 初始阶段的保护，主要是通过抑制细胞死亡和促进炎症消退，这与减轻线粒体功能障碍有关。从机制上讲，P2rx1耗竭可抑制体内 STING-TANK 结合激酶 1 (TBK1)-P65 信号通路。然后，我们发现 DMX 介导的 STING 激活可以极大地加重用 APAP 处理的P2rx1 ^-/-小鼠的肝损伤。

结论

我们的数据证实 P2RX1 在 AILI 期间被诱导，将 P2RX1 鉴定为线粒体功能障碍和 STING 通路的新型调节剂，并提出了一种有前途的 AILI 治疗方法，包括阻断 P2RX1。

图形概要

1. 首次证明了P2rx1缺乏对对乙酰氨基酚性肝损伤（AILI）的保护作用。

2. P2rx1敲除减轻线粒体功能，促进APAP治疗后炎症消退。

3. 首次报道了P2RX1在AILI进展中对STING信号通路的调控。

4. P2RX1 阻断是一种很有前途的 AILI 治疗策略。