The regulation of inflammasome components in monocytes and macrophages from patients with decompensated cirrhosis

Background: Inflammation is a major cause of organ failure and mortality in cirrhosis and acute-on-chronic liver failure (ACLF). One major driver of inflammatory damage in a variety of liver diseases is inflammasome complexes, which control the release of pro-inflammatory cytokines and inflammatory cell death.

Aims: This project aims on investigating regulation of inflammasome activity in cirrhosis and ACLF and its regulation by low-dose genotoxic stress.

Methods: Circulating monocytes and peritoneal macrophages from patients with decompensation of cirrhosis, and monocytes from healthy controls were isolated and treated with different doses of low-dose epirubicin before the stimulation with inflammasome activators in vitro.

Results: Monocytes from patients with ACLF expressed the highest levels of the inflammasome components pro-IL-1β, AIM2 and ASC as compared to monocytes and macrophages from patients without ACLF. Incubation of monocytes with serum from patients with cirrhosis as in contrast to healthy serum increased IL-1β secretion after low-dose LPS and AIM2 activation in vitro. Treatment with low-dose epirubicin prior to inflammasome activation suppressed the inflammasome-mediated IL-1β release in all investigated primary cell types as well in the monocytic cell line THP-1 in a dose-dependent fashion. The down regulation of the inflammasome activation occurred below the threshold of cytotoxicity without quantifiable DNA damage as assessed by gamma-H2AX levels.

Conclusion: Our data suggest a regulation of the monocyte inflammasome in the context of decompensated cirrhosis and ACLF, which can be counteracted by low-dose genotoxic stress.