The role of conventional and liver resident NK cells in drug-induced liver injury and in the regulation of ILC2 cells

• Applicants: Professor Dr. Jan G. Hengstler; Professor Dr. Carsten Watzl
• Subject Area: Immunology ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397052788

The immune system can significantly contribute to liver damage, not only in the context of chronic viral infections, but also during drug induced liver injury (DILI). Here we focus on the role of liver resident (lrNK) and conventional NK cells (cNK) in the context of DILI and on the role of group 2 innate lymphoid cells (ILC2) during liver fibrosis. Our application is based on the hypothesis that NK cells play a dual role in liver injury. Based on our preliminary data we hypothesize that NK cells can contribute to drug-induced liver injury via the killing of hepatocytes after drug-induced up-regulation of ligands for activating NK cell receptors. Additionally, liver injury is associated with an expansion of ILC2 cells, which can contribute to liver fibrosis. Previous publications have shown that the expansion of ILC2 cells can be inhibited by Interferons. Together with our preliminary data we propose that liver NK cells can control and regulate ILC2 cells and thereby reduce liver fibrosis. To test these two hypotheses we have set up several in vivo and in vitro experimental systems using mouse and human liver NK cells in order to comprehensively characterize the interactions between NK cells, hepatocytes and ILC2. The experimental design allows us to directly compare the phenotype and function of conventional circulating cells (cNK) with tissue resident innate lymphocytes (lrNK) and to investigate the function and the dynamics of these cells during liver injury. Our results will be essential to understand how the opposing activities of liver NK cells with their protective effect during fibrosis and their potential pathological impact during drug induced liver injury are balanced.

• DFG Programme: Research Grants