Abstract：
Purinergic P2X4 receptor (P2X4R) has been shown to have immunomodulatory properties in infection, inflammation, and organ damage including liver regeneration and fibrosis. However, the mechanisms and pathophysiology associated with P2X4R during acute liver injury remain unknown. We used P2X4R-/- mice to explore the role of P2X4R in three different models of acute liver injury caused by concanavalin A (ConA), carbon tetrachloride, and acetaminophen. ConA treatment results in an increased expression of P2X4R in the liver of mice, which was positively correlated with higher levels of aspartate aminotransferase and alanine aminotransferase in the serum. However, P2X4R gene ablation significantly reduced the severity of acute hepatitis in mice caused by ConA, but not by carbon tetrachloride or acetaminophen. The protective benefits against immune-mediated acute hepatitis were achieved via modulating inflammation (Interleukin (IL)-1β, IL-6, IL-17A, interferon-γ, tumor necrosis factor-α), oxidative stress (malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase), apoptosis markers (Bax, Bcl-2, and Caspase-3), autophagy biomarkers (LC3, Beclin-1, and p62), and nucleotide oligomerization domain-likereceptorprotein 3(NLRP3) inflammasome-activated pyroptosis markers (NLRP3, Gasdermin D, Caspase-1, ASC, IL-1β). Additionally, administration of P2X4R antagonist (5-BDBD) or agonist (cytidine 5\'-triphosphate) either improved or worsened ConA-induced autoimmune hepatitis, respectively. This study is the first to reveal that the absence of the P2X4 receptor may mitigate immune-mediated liver damage, potentially by restraining inflammation, oxidation, and programmed cell death mechanisms. And highlight P2X4 receptor is essential for ConA-induced acute hepatitis.
摘要：
嘌呤能P2X4受体（P2X4R）已被证明在感染中具有免疫调节特性，炎症,和器官损伤，包括肝再生和纤维化。然而,P2X4R在急性肝损伤中的相关机制和病理生理学尚不清楚.我们使用P2X4R-/-小鼠来探讨P2X4R在三种不同的伴刀豆球蛋白A（ConA）引起的急性肝损伤模型中的作用。四氯化碳，和对乙酰氨基酚.ConA治疗导致小鼠肝脏中P2X4R的表达增加，与血清谷草转氨酶和谷丙转氨酶水平呈正相关。然而,P2X4R基因消融显著降低ConA引起的小鼠急性肝炎的严重程度，但不是四氯化碳或对乙酰氨基酚。通过调节炎症（白细胞介素（IL）-1β，IL-6,IL-17A,干扰素-γ，肿瘤坏死因子-α），氧化应激(丙二醛，超氧化物歧化酶,谷胱甘肽过氧化物酶,和过氧化氢酶)，凋亡标志物(Bax，Bcl-2和Caspase-3），自噬生物标志物（LC3，Beclin-1和p62），和核苷酸寡聚化结构域-类似受体蛋白3（NLRP3）炎症体激活的焦亡标记（NLRP3，GasderminD，Caspase-1,ASC,IL-1β）。此外,P2X4R拮抗剂（5-BDBD）或激动剂（胞苷5'-三磷酸）的给药改善或恶化ConA诱导的自身免疫性肝炎，分别。这项研究首次揭示了P2X4受体的缺失可以减轻免疫介导的肝损伤，可能通过抑制炎症，氧化，和程序性细胞死亡机制。强调P2X4受体对于ConA诱导的急性肝炎至关重要。
