Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China.
Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China.
Int Immunopharmacol. 2023 Mar;116:109808. doi: 10.1016/j.intimp.2023.109808. Epub 2023 Feb 8.
BACKGROUND & AIMS: Silibinin-phospholipid complex (SPC) has been utilized to treat acute liver injury clinically. Nevertheless, the hepatoprotective mechanism of SPC remains to be further dissected in response to new insights into the pathogenesis of acute liver injury. Very recently, we have documented, for the first time, that M2-like macrophages exert the hepatoprotection against acute insult through inhibiting necroptosis-S100A9-necroinflammation. In the present work, we integrated this new finding into the mechanism of action of SPC, and attempted to dissect the hepatoprotective mechanism of SPC from this new perspective.
SPC and corresponding controls were administered intragastrically into control mice subjected to d-GalN/LPS challenge. The hepatic damage was assessed, and the expression of necroptosis-S100A9-necroinflammation signaling molecules was detected. The correlation between SPC and macrophage activation was investigated. The expression of miR-223-3p and its regulation on macrophage activation were analyzed. The targeted inhibitory effects of miR-223-3p on necroptosis and necroinflammation signaling molecules were confirmed.
SPC alleviated remarkably the hepatic damage triggered by d-GalN/LPS. The administration of SPC inhibited the expression of necroptosis-S100A9-necroinflammation signaling molecules. The levels of M2-like macrophage markers were increased significantly in SPC-treated mice or macrophages. miR-223-3p expression was enhanced in SPC-treated mice. miR-223-3p transfer led to up-regulated expression of M2-like macrophage markers. miR-223-3p directly targeted 3' UTR of RIPK3 and NLRP3, and the expression of necroptosis and necroinflammation signaling molecules was inhibited in miR-223-3p-transferred hepatocytes and macrophages.
SPC alleviates acute liver injury through up-regulating the expression of miR-223-3p. MiR-223-3p further promotes M2-like macrophage activation and the targeted inhibition of necroptosis and necroinflammation. Our findings provide novel insight into the hepatoprotective mechanism of SPC against acute liver injury.
水飞蓟宾磷脂复合物（SPC）已被用于临床治疗急性肝损伤。然而，为了深入了解急性肝损伤的发病机制，仍需要进一步研究 SPC 的肝保护机制。最近，我们首次记录到 M2 样巨噬细胞通过抑制坏死性凋亡-S100A9-坏死性炎症来发挥对急性损伤的保护作用。在本工作中，我们将这一新发现纳入 SPC 的作用机制中，并试图从这一新视角剖析 SPC 的肝保护机制。
SPC 和相应的对照品通过灌胃给予 D-半乳糖胺/脂多糖诱导的对照小鼠。评估肝损伤，检测坏死性凋亡-S100A9-坏死性炎症信号分子的表达。研究 SPC 与巨噬细胞激活的相关性。分析 miR-223-3p 的表达及其对巨噬细胞激活的调控。确认 miR-223-3p 对坏死性凋亡和坏死性炎症信号分子的靶向抑制作用。
SPC 显著减轻 D-半乳糖胺/脂多糖诱导的肝损伤。SPC 给药抑制了坏死性凋亡-S100A9-坏死性炎症信号分子的表达。SPC 处理的小鼠或巨噬细胞中 M2 样巨噬细胞标志物的水平显著增加。SPC 处理的小鼠中 miR-223-3p 的表达增强。miR-223-3p 转染导致 M2 样巨噬细胞标志物的表达上调。miR-223-3p 直接靶向 RIPK3 和 NLRP3 的 3'UTR，miR-223-3p 转染的肝细胞和巨噬细胞中坏死性凋亡和坏死性炎症信号分子的表达受到抑制。
SPC 通过上调 miR-223-3p 的表达来减轻急性肝损伤。miR-223-3p 进一步促进 M2 样巨噬细胞的激活，并靶向抑制坏死性凋亡和坏死性炎症。我们的研究结果为 SPC 防治急性肝损伤的肝保护机制提供了新的见解。
