Beijing Institute of Hepatology/Beijing Youan Hospital, Capital Medical University, Beijing, China.
Front Immunol. 2024 May 22;15:1381735. doi: 10.3389/fimmu.2024.1381735. eCollection 2024.
Acute liver injury (ALI), which is a type of inflammation-mediated hepatocellular injury, is a clinical syndrome that results from hepatocellular apoptosis and hemorrhagic necrosis. Apoptosis stimulating protein of p53-2 (ASPP2) is a proapoptotic member of the p53 binding protein family. However, the role of ASPP2 in the pathogenesis of ALI and its regulatory mechanisms remain unclear.
The expression of ASPP2 were compared between liver biopsies derived from patients with CHB, patients with ALI, and normal controls. Acute liver injury was modelled in mice by administration of D-GalN/LPS. Liver injury was demonstrated by serum transaminases and histological assessment of liver sections. ASPP2-knockdown mice (ASPP2) were used to determine its role in acute liver injury. Mouse bone marrow macrophages (BMMs) were isolated from wildtype and ASPP2 mice and stimulated with LPS, and the supernatant was collected to incubate with the primary hepatocytes. Quantitative real-time PCR and western blot were used to analyze the expression level of target.
The expression of ASPP2 was significantly upregulated in the liver tissue of ALI patients and acute liver injury mice. ASPP2 mice significantly relieved liver injury through reducing liver inflammation and decreasing hepatocyte apoptosis. Moreover, the conditioned medium (CM) of ASPP2 bone marrow-derived macrophages (BMMs) protected hepatocytes against apoptosis. Mechanistically, we revealed that ASPP2 deficiency in BMMs specifically upregulated IL-6 through autophagy activation, which decreased the level of TNF-α to reduce hepatocytes apoptosis. Furthermore, up-regulation of ASPP2 sensitizes hepatocytes to TNF-α-induced apoptosis.
Our novel findings show the critical role of ASPP2 in inflammatory immunoregulatory mechanism of ALI and provide a rationale to target ASPP2 as a refined therapeutic strategy to ameliorate acute liver injury.
急性肝损伤（ALI）是一种炎症介导的肝细胞损伤，是一种由肝细胞凋亡和出血坏死引起的临床综合征。p53 结合蛋白家族的促凋亡成员 p53 凋亡刺激蛋白 2（ASPP2）。然而，ASPP2 在 ALI 发病机制中的作用及其调节机制尚不清楚。
比较了来自慢性乙型肝炎患者、ALI 患者和正常对照者的肝活检中 ASPP2 的表达。通过给予 D-GalN/LPS 建立急性肝损伤小鼠模型。通过血清转氨酶和肝组织学评估来证明肝损伤。使用 ASPP2 敲除小鼠（ASPP2）来确定其在急性肝损伤中的作用。从野生型和 ASPP2 小鼠中分离出骨髓巨噬细胞（BMM），并用 LPS 刺激，收集上清液孵育原代肝细胞。用定量实时 PCR 和 Western blot 分析靶标表达水平。
ASPP2 在 ALI 患者和急性肝损伤小鼠的肝组织中表达明显上调。ASPP2 小鼠通过减少肝炎症和减少肝细胞凋亡显著缓解肝损伤。此外，ASPP2 骨髓来源巨噬细胞（BMM）的条件培养基（CM）可保护肝细胞免受凋亡。在机制上，我们揭示了 BMM 中 ASPP2 缺乏可通过自噬激活特异性地上调 IL-6，从而降低 TNF-α水平，减少肝细胞凋亡。此外，ASPP2 的上调使肝细胞对 TNF-α诱导的凋亡敏感。
我们的新发现表明 ASPP2 在 ALI 的炎症免疫调节机制中起着关键作用，并为靶向 ASPP2 作为改善急性肝损伤的精细治疗策略提供了依据。
