Author:
Guan Zeliang,Ding Yun,Liu Yongai,Zhang Yu,Zhao Jingmin,Li Changfei,Li Zihai,Meng Songdong
Abstract
AbstractLiver 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.
Funder
Strategic Priority Research Program of the Chinese Academy of Sciences
One Belt and One Road International Science and Technology Cooperation of Chinese Academy of Sciences
National Natural Science Foundation of China
the Industrial innovation team grant from Foshan Industrial Technology Research Institute, Chinese Academy of Sciences
Publisher
Springer Science and Business Media LLC
Cited by
7 articles.
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