Epigenetic regulation of inflammation by human peritoneal macrophages in patients with liver cirrhosis

• Applicant: Dr. Sven Stengel
• Subject Area: Gastroenterology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451864437

Decompensated liver cirrhosis (DLC) represents the final stage of chronic liver disease and is characterized by high mortality rates. This is mainly due to bacterial infections, which on the one hand result from an increased translocation of bacteria from the intestine into the circulation and on the other hand are favoured by the cirrhosis-related immunodeficiency. Antibiotics are used to prevent bacterial infections in high-risk patients, which is associated with an increased risk of resistance. This correlation is also apparent in the increasing number of new infections with multi-resistant germs. One possible way out of this dilemma is the development of new antimicrobial or immunomodulatory therapies. As we have shown in previous studies, the complications of liver cirrhosis affect the phenotypic and functional design of immune cells. Especially monocytes and peritoneal macrophages show an increased immunological activation in patients with liver cirrhosis. After pathogen detection these cells secrete increased amounts of TNF and CD206 compared to healthy donors. Increased activation of inflammation is associated with reduced survival following spontaneous bacterial peritonitis (SBP). Peritoneal macrophages from cirrhosis patients exhibit a more pronounced pro-inflammatory differentiation status compared to cells from healthy donors.Our own preliminary work shows that differentiation processes and by that the function of peritoneal macrophages can be shaped by nuclear receptor agonists. Furthermore, our results illustrate that the activation of Toll-like receptors (TLR) induce epigenetic changes of the macrophage genome. Also, the expression of epigenetic regulators such as EZH2 and KDM6B are affected . In line with this, inhibition of EZH2 and KDM6B by small molecular compounds leads to altered cytokine profiles in human peritoneal macrophages.The aim of this proposal is to decipher cirrhosis-related changes in the epigenetic landscape of human peritoneal macrophages and monocytes in order to identify new targets for therapies and new markers for the identification of high-risk patients. In addition, we will investigate how nuclear receptor agonists and epigenetic inhibitors can be used to modulate the induction of inflammation by human peritoneal macrophages. The findings of the proposed study can pave the way for the development of new treatment strategies to mitigate the consequences of bacterial infections and to increase long-term survival of patients suffering from decompensated liver cirrhosis.

• DFG Programme: Research Grants