The context-dependent role of IL-22 in chronic liver disease and acute-on-chronic liver failure

• Applicants: Dr. Katharina Maria Schwarzkopf; Professor Dr. Christoph Welsch
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524039901

Liver cirrhosis is recognized worldwide with high prevalence and mortality. Patients with end-stage liver disease, independent of the underlying etiology, can develop acute-on-chronic liver failure (ACLF) as a severe complication characterized by hepatic and extrahepatic organ failures, comprising kidney, circulation and pulmonary failure. Mortality rates up to 79% within 90 days have been observed. Established precipitating events of ACLF include infections, excessive alcohol consumption, exposure to toxins and bleeding episodes. These events are able to strongly augment the liver cirrhosis-associated systemic inflammatory response, characterized by high levels of proinflammatory and antiinflammatory cytokines, switch of monocyte phenotypes, and immune paralysis. To date, no targeted (specific) therapeutic options are available. Cytokines play key roles in controlling immune responses and promoting tissue homeostasis. Thereby, most cytokines elicit distinct and often opposing effects depending on the biological context. This functional diversity is also evident in IL-22 which is a key player in antimicrobial defense, regeneration and chronic inflammation with either a protective or pathogenetic role. We could show that high levels of IL-22 are associated with ACLF and mortality in patients with advanced-stage liver disease and cirrhosis. In contrast IL-22 seems to be beneficial in animal models of acute liver injury. These opposing effects could in part be explained from modulation on the cytokine receptor level. Thereby, expression levels of diverse cytokines and their receptors and ability to simultaneously activate multiple intracellular signaling pathways in target cells determine downstream signaling phenotypes. Activity and functionality of endogenous IL-22 is unknown in chronic liver disease as well as mechanisms related to the regulation of signal transduction. Aim of the present project is hence to analyze and characterize the function of endogenous IL-22 in mouse models of chronic liver disease and ACLF and determine IL-22 signaling phenotypes dependent on the local cytokine milieu in the liver in different stages of chronic liver disease, in acute decompensation and ACLF. Our research proposal is based on mouse models that we developed to mimic different disease etiologies and IL-22 knockout mice, complemented by cell culture studies comprising primary (isolated) cells and validation of experimental findings in clinical cohorts. We hypothesize that although IL-22 expression levels correlate with poor outcome, IL-22 function is potentially hepatoprotective, depending on the stage of liver disease. We speculate that functional diversity in IL-22 signaling is differentially regulated on the IL-22 receptor level dependent on the local cytokine milieu in different stages of liver disease.

• DFG Programme: Research Grants