Monocytes represent about 5-10% of blood leukocytes and are established circulating precursors for tissue macrophages and dendritic cells (DCs). Monocytes that are recruited into the injured liver and monocyte-derived macrophages have been identified as essential regulators of inflammatory processes during acute and chronic liver injury. Monocytes consist of at least two major subpopulations that differ in migratory properties, differentiation and function. Our group aims at characterizing the role of monocyte and macrophage subsets in liver inflammation and liver fibrosis. A particular focus are non-alcoholic fatty liver diseases and the metabolic syndrome. In order to identify immune cell subsets and characterize their functional properties in the liver we apply multiple innovative techniques as single cell RNA sequencing, FACS-based sorting, multicolor flow cytometry and high throughput gene expression analysis.
The infiltration of immune cell subsets and their subsequent activation are crucial mechanisms in acute and chronic liver inflammation. However, the cascade of molecular and cellular events that initiate inflammation in injured liver is incompletely understood. Currently, the group is focussing on the function of infiltrating monocytes and resident liver macrophages (Kupffer cells) and their contribution to liver inflammation and wound healing as well as their role in the priming and crosstalk to cells of the adaptive immune response. To this end, we have established an imaging system based on intravital two-photon laser-scanning microscopy (TPLSM), a novel imaging technology that allows in vivo tracking of migrating labelled cells into injured organs such as liver, kidney, gut and bladder (Fig.1). As a complementary method, tissue clearing allows high resolution tomographic microscopy imaging of explanted tissues. Our approach to combine those imaging techniques with multicolour flow cytometry, RNA expression analysis (including single cell RNA sequencing) and spectrometry protein analysis enables us to study cellular interactions (infiltrating immune cells – resident hepatic cell compartments) and molecular pathways of monocytes and other immune cells in the initiation, progression and resolution of inflammatory responses to organ damage. The analyses are anticipated to identify novel anti-inflammatory therapeutic targets in liver disease and furthermore broaden the general understanding of chronic inflammatory diseases as such.
Dr. rer. nat. Felix Heymann
Figure 1 TPLSM Image of Kupffer cells (pink) and liver dendritic cells (green)
Monocytes and macrophages (MΦs) fulfil critical decisive roles in inflammatory and malignant disorders, because their activation and differentiation crucially determine the perpetuation or restriction of inflammation: pro-inflammatory M1 MΦs promote inflammation but also antitumoral responses, whereas anti-inflammatory M2 MΦs and myeloid-derived suppressor cells (MDSC) restrict local and systemic inflammation but promote tumor growth. The modification of macrophage functionality, particularly in the liver, appears to be a promising novel therapeutic target for inflammatory disorders, fibrosis and cancer. Many different, mostly nano-sized drug carrier systems have been developed over the years, which are often also biofunctionalized with antibodies or peptides. Prior in-vitro data demonstrated that human macrophages can be skewed towards M1- or M2-effector macrophages by distinct biofunctionalized gold nanorods. We investigate different nanoparticle-based approaches in murine inflammation, fibrosis and cancer models, with a focus on biodistribution, toxicity, macrophage polarization and impact on disease in preventive or therapeutic administrations in vivo.
Dr. rer. nat. Matthias Bartneck
Hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide, commonly arises as a consequence of chronic liver damage, resulting in inflammatory responses. Patients with chronic liver inflammation, typically undergo a steady progression of the disease leading to the development of liver fibrosis, cirrhosis and finally, HCC. Knowledge of the exact mechanisms of the inflammatory processes as well as the phenotype of the contributing immune cells is crucial to ensure that pharmacological treatment of the disease is beneficial for all patients. We are applying innovative techniques for the identification and labelling of immune cell subsets as well as for their isolation (FACS-based sorting) and functional characterization (NanoString, single cell RNA Seq).
Dr. rer. nat. Anke Pfeiffer
Although chronic liver disease has many etiologies, including chronic viral hepatitis, alcohol abuse, metabolic syndrome, and autoimmune disorders, the cellular and pathological mechanisms leading to liver fibrosis and – as an end-stage – cirrhosis are relatively common and uniform. However, eradication of the underlying disease, e.g. chronic virus hepatitis, is currently unattainable in many patients – and liver transplantation remains the only curative treatment option in a number of cases. Our group therefore studies possible pathogenetic factors in blood and liver samples of patients with chronic liver disease, e.g. immune or inflammatory mediators, in order to unravel novel diagnostic or prognostic indicators as well as potential targets for future therapies. A particular interest are critically ill patients (e.g., with acute-on-chronic liver failure) that are being managed at the intensive care unit.
Persistent infection with the hepatitis B virus (HBV) represents a major health problem worldwide with over 240 million patients at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double stranded DNA virus with four overlapping genes. Mutations occur frequently during chronic infection and can tremendously affect the clinical outcome. Projects in our lab characterize the molecular mechanisms by which different, clinically relevant mutations affect the replication efficacy of the virus and its sensitivity to antiviral drugs, using replication-competent HBV constructs in cell culture. We further characterize molecular interactions between HBV and Hepatitis D Virus (delta hepatitis).