GUT-DERIVED LIPOPOLYSACCHARIDE: THE INITIATOR OF THE CYTOKINE STORMS IN ACUTE-ON-CHRONIC LIVER FAILURE

Objective:

Clinical patients with acute-on-chronic liver failure (ACLF) often exhibit a high short-term mortality. Hyperactivation of immune cells and elevated circulating cytokines levels, which was termed as cytokine storms, is related to the high mortality. However, the pathogenesis of how cytokine storms were shaped in ACLF patients and their roles in the development of ACLF still remain unknown.

Methods:

In this study, we established a sepsis-induced ACLF mouse model by combining chronic liver injury, acute hepatic insult and cecal ligation and puncturing. Kupffer cells-conditional Gsdmd knockout mice (Clec4fcreGsdmdfl/fl) and germ-free mice were used in rescue experiments. Meanwhile, serum samples from clinical ACLF patients were also collected and assessed.

Results:

Inflammatory cytokines IL-6, TNF-α, IFN-γ and IL-1β were extremely high after acute hepatic insult both in human and mice. Pyroptosis in Kupffer cells, which was induced by gut microbes-derived LPS, initiated the cytokine storms. Liver bacterial translocation and gut-derived LPS activated canonical inflammasome signaling in Kupffer cells, which resulted in the release of DAMPs and was followed by immune response activation and piecemeal necrosis of hepatocytes. Specific knockout of Gsdmd in Kupffer cells switched hepatocytes from necrosis to apoptosis and abolished the release of pro-inflammatory cytokines. Meanwhile, pathogen deficiency rescued the cleavage of GSDMD and inhibited the occurrence of cytokine storms, verified that gut microbes-derived LPS was the initiator.

Conclusions:

Gut-derived LPS induced pyroptosis in Kupffer cells and triggered inflammatory cytokine cascade in ACLF.