Einleitung: HCV ist trotz der Entwicklung suffizienter Therapieoptionen weltweit unverändert eine der Hauptursachen chronischer Lebererkrankungen und Risikofaktor für hepatozelluläre Karzinome. Bei bis zu 70% der Infizierten persistiert das Virus, trotz anhaltender Replikation, zumeist über viele Jahrzehnte mit asymptomatischem Verlauf. Dieser Verlauf legt nahe, dass HCV die entzündliche wie auch die antivirale Reaktion des Wirtes zu unterlaufen vermag. Ziel dieser Arbeit ist die weitergehende Aufklärung der Mechanismen, die es HCV ermöglichen, die interzelluläre Kommunikation der Wirtszelle im Kontext von diskreten Entzündungsreaktionen zu beeinflussen.

Background & aims In the context of liver regeneration macrophages play an important regulatory role. Thereby the changes of the composition of the different macrophage populations and of their polarization during liver regeneration has not been investigated in detail. Likewise, the factors that mainly control this process as well as their relevance for undisturbed regeneration are unclear.

Background & aims The Hepatitis C Virus (HCV) has developed several strategies to persist in infected cells without being cleared by the immune system. HCV intervenes in various cellular processes, e.g. via cleavage of host proteins. Transgenic mice expressing the viral protease NS3/4A are protected against LPS challenge due to elevated TNFα levels. Both TNFα and IL-1β are known to be upregulated in sera of HCV-infected patients. Recently, we were able to show that HCV further upregulates EGF-induced CXC chemokine expression. The present study aims to analyse the influence of the cytokines TNFα and IL-1β on the CXC chemokine expression pattern of HCV infected cells.

Einleitung TGFβ ist an der Regulation entzündlicher Prozesse beteiligt. Da der Verlauf entzündlicher und auch regenerativer Prozesse im Körper maßgeblich durch Immunzellen reguliert wird und hierbei Makrophagen, die sich ihrem jeweiligen Mikromilieu anpassen, eine wichtige Rolle spielen, ist der Einfluss von TGFβ auf diese Zellen von besonderem Interesse.

Background & aims Cytomegalovirus (CMV) circumvents sterile immunity and establishes a state of latency from which the virus reactivates under immunosuppressive conditions causing substantial morbidity and mortality. Multiple organs are targets of CMV infection, however the liver represents a prime site of CMV replication and latency. We could recently demonstrate that an acute infection with murine (M)CMV induces activation of the MAPKAP kinase (MK)2, which is critical for the generation of a cytokine response to MCMV and drives an IFNAR1-dependent circuit that controls IL-10 production and limits aggregation of CD11b+ myeloid cells in the liver. These intrahepatic myeloid-cell aggregates recruit cytotoxic CD8+ T cells and enable their local expansion without causing severe liver pathology. Aim of this study is to understand the MK2-controlled mechanisms that regulate formation of these myeloid-cell aggregates and influence viral replication. Moreover, the role of MK2’s homologous kinase MK3, previously unexplored in this context, should be clarified.

Background Both internationally and in Germany, liver transplantation (LT) has undergone a dynamic development in recent decades. This has included a complete change in the allocation system with the introduction of the MELD-system, but also challenges such as those arising from the irregularities at four German liver transplant centers exposed in 2012. In addition, there is an ongoing discussion in Germany about the total number of centers at which LT is carried out and the Joint Federal Committee (G-BA) has recently reinforced the guidelines regarding minimum transplantation numbers. A systematic evaluation of existing data sets and their careful interpretation can support a rational discussion aiming at optimizing framework conditions of LT.

Background & aims Macrophages are key components of the innate immune response. With high plasticity they adapt their phenotype to distinct challenges. As first responders towards pathogens they express inflammatory cytokines and chemokines that regulate responses of the cellular microenvironment within the liver. Hepatocytes represent a prime site of viral replication upon cytomegalovirus (CMV) infection. So far it is unknown, how macrophages impede viral replication in hepatocytes or if at all. Contrariwise, the impact of hepatocytes on the macrophages” phenotype in case of CMV infection remains to be elucidated. In addition, similarities or differences between co-cultivated macrophages and hepatocytes after treatment with CMV or lipopolysaccharide (LPS) are not identified, yet. First, this study aims to evaluate the pathogen-induced molecular pattern that directs the intercellular communication between macrophages and hepatocytes. Second, the impact of macrophages on viral replication within hepatocytes is analyzed.

Introduction Infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has developed into a pandemic with millions of infected people worldwide. Although an elevation of liver enzymes has often been observed especially in severe cases, we were able to document the first case of secondary sclerosing cholangitis (SSC) after coronavirus disease 2019 (COVID-19). The correlation between hepatobiliary injury and the infection is not fully understood yet.

Background & aims The liver contributes to innate immunity towards pathogens by the synthesis of acute phase proteins (APP). These proteins minimize tissue damage and promote repair processes. They isolate and neutralize invading pathogens and prevent further pathogen entry. Some of them including the antimicrobial peptide hepcidin also maintain iron homeostasis. The expression of APP by hepatocytes is regulated by inflammatory cytokines and chemokines, which are released by non-parenchymal cells like macrophages and tightly controlled by the intracellular MAPKAP kinase (MK)2. So far, it is unknown, if MK2 plays a role for the synthesis of APP in the liver. Aim of this study is to reveal MK2-dependent mechanisms involved in the regulation of APP and in particular hepcidin expression.

The macrophage populations of the liver are heterogeneous, consisting of self-renewing tissue-resident macrophages and monocyte-derived macrophages (moMΦ) recruited from the circulation. After liver injury particularly the recruitment of moMΦ population is considered to be important for undisturbed regeneration. However, up to now it is unclear in how far an environment that is predominantly shaped by hepatocyte-derived factors influence macrophage polarization and function.

The Hepatitis C Virus (HCV) employs several strategies to circumvent the antiviral immune response of its host. This also involves modulation of the local and systemic inflammatory response of the host. As it is known that serum levels of inflammatory cytokines such as Interleukin 1β (IL-1β) are upregulated in sera of HCV-infected patients, the present study analyses the impact of HCV on chemokine expression and in particular on the expression of CXCR2 ligands of its host cell in response to stimulation with IL-1β.

Cholestasis is a common complication in patients with sepsis and systemic inflammatory response syndrome. In this context IL1β and TNFα mediated downregulation of the expression of the bile salt export pump (BSEP) is known to be important (Luster et al., 1994, Roelofsen et al., 1995). However, the importance of the relevance of chemokines in this regard is unclear, and the elucidation of their significance for the inhibition of bile-salt-induced upregulation of the expression of BSEP is the subject of the present studies.

HCV has evolved powerful mechanisms to manipulate antiviral and innate immunity and to interfere with the inflammatory host response. Thereby the local composition of inflammatory and immune cells is largely determined by the pattern of chemokines released from the different cell types of the liver. We could recently demonstrate that HCV enhances basal and EGF-dependent expression of the chemokines CXCL1, 2, 3 and 8 (Groepper et al., 2018). The present study investigates the influence of HCV on inducible expression of these chemokines in response to the inflammatory cytokines TNFα and IL-1β either alone or in combination.

In ihrer Rolle als Immunorgan spielt die Leber eine wichtige Rolle für die Akutphase-Antwort, in deren Verlauf in den Hepatozyten Akutphase-Proteine synthetisiert werden. Diese Synthese wird induziert z.B. durch das bakterielle Endotoxin Lipopolysaccharid (LPS) und vermittelt über die Expression inflammatorischer Zytokine, wie IL-6 und IL-1beta. In diesem Zusammenhang ist die MAPKAP-Kinase (MK)2 ein wichtiger intrazellulärer Mediator der Zytokin-Expression. Welchen Einfluss diese Kinase auf die Expression von Akutphase-Proteinen ausübt, ist allerdings bisher noch unbekannt. Ein Verständnis der hierbei beteiligten molekularen Mechanismen ist wichtig für die Entwicklung von Therapien zur Auflösung des Entzündungsgeschehens sowie zur Leberregeneration nach Schädigung durch Pathogene.