In addition to its central role in the metabolism of proteins, fats and carbohydrates, the disposal and excretion of metabolic waste products and detoxification, the liver is also of central importance as an immunological organ. Here, it plays an important role in the development of immune tolerance and in the control of the innate and adaptive immune response. For example, as the major producer of acute phase proteins, it plays a key role in the control of acute phase responses and is thus an important component in the development and control of inflammatory and immune responses. In addition, the liver harbors a variety of immune cell populations, such as the largest pool of tissue-resident macrophages. In particular, the latter are of central importance in this context, both for the maintenance of homeostasis and in the context of pathological processes.
The Hepatoimmunology group studies the molecular inter- and intracellular communication networks by which the liver regulates systemic inflammation and immunity. In this context, the focus is also on the dysregulation of these networks by metabolic, inflammatory or infectious factors that lead to the development of chronic liver diseases, failure of repair processes or insufficient immune responses.
Here, the research group is currently addressing the following two topics:
- intra- and intercellular processing and interconnection of signaling networks activated by cytokines and pathogens in non-parenchymal (figure 1) and parenchymal cells of the liver (figure 2); importance and role of their dysfunction in the context of regeneration processes, pathogenesis and progression of metabolic liver diseases.
- influence of pathogens, especially hepatitis C virus and cytomegalovirus, on cellular decision-making processes in the host cell (figure 3); their effects on the immunological milieu and their importance of these interactions for antiviral immunity and establishment of viral persistence.
An important topic we are currently addressing in the context of issue a) is the change in the activation state of the different macrophage populations of the liver under the influence of the molecular and cellular environment. Here, we are interested in the relevance of this reciprocal relationship for the course of regeneration processes or metabolic liver diseases. Thereby, our data suggest that, depending on their origin, the macrophage populations of the liver already exhibit significant differences in their activation states under homeostatic conditions. The presence of a microenvironment dominated by hepatocytes plays an intriguing role in eliciting this particular activation state. It is therefore quite conceivable that disturbances in hepatocyte function have a particular impact on the macrophage’s activation state and thus on their response to physiological or pathogenic stimuli. It is also likely that this further influences the regulation of the acute-phase response, since the inflammatory response of liver macrophages is considered to be critical for the control of acute-phase protein production by hepatocytes. In this regard, the group is also interested in the cell type-specific importance of p38MAPK and its two effector kinases MK2 and MK3, which are known to be central for the production of a variety of cytokines.
Viruses capable of establishing persistent infections in their host must have developed mechanisms during co-evolution that allow them to subvert the host's antiviral immunity and exploit the host's infrastructure without compromising its viability. In this context, the capability of viruses such as hepatitis C virus and cytomegalovirus to interfere with host signaling pathways and thereby alter or even reprogram host cell behavior is of great importance. Previous work indicates that hepatitis C virus in particular is capable of literally reprogramming the intra- and intercellular signaling networks of the hepatocyte, thereby affecting the immunological milieu of the liver. This aspect is currently being further investigated in the context of issue b) by a DFG-funded project. In addition, we are addressing the cell type-specific relevance of the MK2/MK3 system for the immune control of cytomegalovirus and the interference of the virus with this signaling pathway.