Universitätsklinikum Hamburg-Eppendorf

Zentrum für Experimentelle Medizin – Institut für Experimentelle Immunologie und Hepatologie

Role of type 2 innate lymphoid cells in immune-mediated liver disease and liver regeneration

Chronic liver diseases are a global health problem with limited therapeutic options so far. The immune-mediated processes leading to chronic inflammation, development of fibrosis, cirrhosis, and subsequent hepatocellular carcinoma (HCC) are still poorly understood. Innate lymphoid cells (ILC) are a group of lymphocytes of the innate immune system that rapidly produce cytokines upon activation thereby contributing to immune responses during infection and inflammation. We could show that type 2 ILC (ILC2) exert a pro-inflammatory function in acute, immune-mediated hepatitis and aggravate liver inflammation and tissue damage. In the proposed project, we further want to analyze the role of ILC2 in liver inflammation, with a special focus on chronic liver disease and development of HCC. We also want to study the impact of hepatic ILC2 on the function of macrophages in acute and chronic liver injury since this cell population plays an important role in the pathology of liver diseases. Moreover, we want to identify liver-specific mechanisms by which the inflammatory activity of hepatic ILC2 is regulated in acute and chronic liver disease to reveal potential strategies for a selective targeting of ILC2-mediated immune responses in the liver. In addition, we want to investigate whether hepatic ILC2 also exert regenerative functions in the liver. Therefore, we want to analyze if ILC2 contribute to regenerative processes after acute liver injury and in the context of chronic liver disease and HCC development by production of amphiregulin. For our analysis, we want to use different murine models of acute and chronic liver disease, liver regeneration and HCC. In in-vitro experiments, we will further study mechanisms of mutual influence of hepatic ILC2 and liver-resident cell populations. Moreover, we want to characterize ILC subsets in blood and liver samples of patients with autoimmune hepatitis, primary sclerosing cholangitis, and alcohol-induced liver cirrhosis with regard to their frequency, activity, and cytokine production. The project allows a deeper understanding of ILC2-mediated immune responses in liver inflammation and therefore, makes an important contribution for the identification of immune-mediated processes involved in the pathogenesis of liver diseases.