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

慢性肝病是一个全球性的健康问题，迄今为止治疗选择有限。导致慢性炎症、纤维化、肝硬化和随后的肝细胞癌（HCC）的免疫介导的过程仍然知之甚少。先天性淋巴样细胞（ILC）是先天免疫系统的一组淋巴细胞，其在激活时快速产生细胞因子，从而在感染和炎症期间促进免疫应答。我们可以证明2型ILC（ILC2）在急性免疫介导的肝炎中发挥促炎作用，并加重肝脏炎症和组织损伤。在拟议的项目中，我们进一步分析ILC2在肝脏炎症中的作用，特别关注慢性肝病和HCC的发展。我们还想研究肝脏ILC2对急性和慢性肝损伤中巨噬细胞功能的影响，因为该细胞群在肝脏疾病的病理学中起着重要作用。此外，我们希望确定肝脏特异性机制，通过该机制在急性和慢性肝病中调节肝脏ILC2的炎症活性，以揭示选择性靶向肝脏中ILC2介导的免疫应答的潜在策略。此外，我们想研究肝脏ILC2是否也在肝脏中发挥再生功能。因此，我们想分析ILC2是否有助于急性肝损伤后的再生过程，以及在慢性肝病和HCC发展的背景下通过产生双调蛋白。对于我们的分析，我们希望使用急性和慢性肝病，肝再生和HCC的不同小鼠模型。在体外实验中，我们将进一步研究肝脏ILC2和肝脏驻留细胞群相互影响的机制。此外，我们希望在自身免疫性肝炎、原发性硬化性胆管炎和酒精诱导的肝硬化患者的血液和肝脏样本中描述ILC亚群的频率、活性和细胞因子产生。该项目可以更深入地了解肝脏炎症中ILC2介导的免疫反应，因此，为识别参与肝脏疾病发病机制的免疫介导过程做出了重要贡献。

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.