Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage
Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage
复制标题
细胞外 gp96 是驱动免疫过度激活和肝损伤的关键介质
DOI：
10.1038/s41598-020-69517-7
复制
发表时间：
2020-07-28
影响因子：
4.6
通讯作者：
Meng, Songdong
中科院分区：
文献类型：
--
作者：
Guan, Zeliang;Ding, Yun;Meng, Songdong
肝功能衰竭会导致肝细胞大量坏死，释放出大量细胞内成分，其中包括损伤相关分子模式（DAMPs）。我们发现，慢性乙型肝炎感染（CHB）和慢加急性肝功能衰竭（ACLF）患者血清中的细胞外gp96水平升高。同时，gp96水平与肝脏坏死性炎症呈正相关。我们采用了脂多糖（LPS）加D - 半乳糖胺（D - Galn）以及刀豆蛋白A（ConA）诱导的两种小鼠肝损伤和肝功能衰竭模型，以确定细胞外gp96的功能。结果显示，一种特异性肽对细胞外gp96的抑制可有效减轻LPS / D - Galn和ConA诱导的肝损伤及免疫过度激活，而外源性gp96会加重小鼠的肝损伤症状，但在枯否细胞被清除的小鼠中则不会。枯否细胞暴露于gp96会诱导促炎细胞因子的分泌。总体而言，我们的数据表明，坏死肝细胞释放的gp96主要通过激活枯否细胞，加剧免疫过度激活，促进肝损伤，并可能推动肝功能衰竭的发展。
Liver failure leads to the massive necrosis of hepatocytes, releasing large amounts of intracellular components including damage-associated molecular patterns (DAMPs). We found that extracellular gp96 levels in serum were elevated in patients with chronic hepatitis B infection (CHB) and acute-on-chronic liver failure (ACLF). Meanwhile, the gp96 level positively correlated with hepatic necroinflammation. We employed two mouse liver damage and liver failure models induced by lipopolysaccharide (LPS) plus d-galactosamine (d-Galn), and concanavalin A (ConA) to identify the function of extracellular gp96. As a result, the inhibition of extracellular gp96 by a specific peptide efficiently mitigated both LPS/d-Galn- and ConA-induced liver injury and immune hyperactivation, whereas exogenous gp96 aggravated the symptoms of hepatic injury in mice but not in Kupffer cells-ablated mice. The exposure of Kupffer cells to gp96 induced the secretion of pro-inflammatory cytokines. Collectively, our data demonstrate that gp96 released from necrotic hepatocytes aggravates immune hyperactivation and promotes liver damage and possibly the development of liver failure mainly by activating Kupffer cells.