Research Area B – Inflammation & fibrosis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, affecting a staggering 30% of the general population.  Its prevalence is expected to rise further with an ageing and more obese world population. MASLD constitutes a major cause of life-threatening sequelae such as liver cirrhosis or hepatocellular carcinoma. While lifestyle interventions have demonstrated some efficacy, no liver-targeted therapy is currently approved. The Transregio-CRC (CRC/TR) on MASLD will focus on understanding, preventing and treating MASLD before the development of late stage complications such as decompensated liver cirrhosis or hepatocellular carcinoma. Our consortium seeks to leverage innovative technologies including single-cell and spatial transcriptomics, lipidomics and organoid modelling, together with outstanding immunological, clinical and translational expertise, to provide yet unprecedented insight into MASLD-driving cell interactions and pathomechanisms in patients, followed by subsequent functional validation as well as testing of new therapies in experimental models. Taking advantage of these advances, our interdisciplinary research consortium will focus on a bidirectional bedside-to-bench and bench-to-bedside approach defining and targeting mechanisms that drive the transition from a solely metabolic risk to a disease with liver-specific sequelae and grave prognostic relevance. 

The overarching aim is to gain a holistic understanding of the disease-defining, liver-specific molecular and cellular events in metabolic dysfunction-associated steatotic liver disease.  

Projects in two interrelated research areas (A – metabolic injury, B – inflammation and fibrosis) will aim at understanding heterogeneity in mechanisms of hepatocyte metabolic injury, subsequent inflammatory and fibrogenic responses as well as the underlying cell-cell crosstalk in order to develop novel therapeutic concepts. Central projects will provide relevant cross-sectional technologies such as access to extensively phenotyped patient material, transcriptomics, bioinformatics, science data management and an integrated research training group. Together, we will define the events that govern the transition from benign steatosis to non-alcoholic steatohepatitis (MASH) and the involved key players; understand key drivers of hepatic inflammation and fibrogenesis in MASLD; elucidate the cross-talk between different cell-types and metabolism – inflammation – fibrosis as well as interrelated feed-forward mechanisms in NAFLD; and apply the above concepts to develop novel therapeutic approaches and concepts of multi-modal combination therapy in MASLD.  

The CRC/TR 412 in Berlin and Dresden will open prospects for a new generation of rationally designed and personalized treatment approaches that might prevent the liver of at risk individuals progress from metabolic risk to disease. 

Portal zonation is a common histologic feature of pediatric MASH and is associated with a progressive disease course. At this time, the mechanisms defining zonal MASH phenotypes are not resolved yet. We will analyze the metabolic, inflammatory and fibrogenic signatures associated with portal and centrilobular disease phenotypes in a comprehensively characterized cohort of children and adolescents with MASLD, applying multiplex immunostaining, single-nucleus sequencing and spatial transcriptomics. Mechanistic studies will be performed in patient-derived iPSC lines and organoids of the very same cohort to further validate newly identified therapeutic strategies. 

PIs: Christian Hudert / Philip Bufler

Liver macrophages are central in the pathogenesis of non-alcoholic fatty liver disease (MASLD). We will characterize the phenotypic, spatial and functional heterogeneity of macrophages including cell-cell interactions and identify targetable ligand-receptor pairs by state-of-the-art technologies on human liver, particularly single-cell RNA sequencing and spatial transcriptomics, in conjunction with functional studies in MASLD mouse models and co-culture systems (‘liver-on-a-chip’). Our findings will provide a comprehensive picture of how hepatic macrophage subsets contribute to altered metabolism, inflammation and fibrosis in MASLD and opportunities for novel therapeutic strategies.

PI: Frank Tacke

The close crosstalk between hepatocytes and macrophages within the lipid-rich liver microenvironment is a central hub in pathogenesis of non-alcoholic fatty liver disease (MASLD) as well as its resolution. Here we will focus on phospholipid phosphatase 3 (PLPP3), which regulates lipid metabolism by dephosphorylation of several lipid substrates. We will study the role of PLPP3 in hepatocytes and macrophages in the context of MASLD pathogenesis and resolution, by using appropriate genetically modified mice and state-of-the-art tools. 

PI: Triantafyllos Chavakis

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form metabolic dysfunction-associated steatohepatitis (MASH) develop as a result of a complex interplay between metabolic injury and inflammation. Dendritic cells (DCs) are crucial mediators of immune responses, and their importance has been recognized for many inflammatory conditions, but their exact role in MASLD/MASH remains largely unclear.    

B04 will systematically investigate the influence of the altered lipidome on DC function in MASLD/MASH, offering novel insights into the immune-metabolic crosstalk that drives these diseases. 

By characterizing the lipid-DC axis in detail and testing its functional implications, this project has the potential to uncover new therapeutic targets for modulating immune responses in MASLD/MASH. 

PIs: Linda Hammerich / Leke Wiering

Macrophage cellular therapy is emerging as a promising new approach for liver metabolic diseases. We will generate autologous macrophages with defined activation and use state-of-the art technologies, particularly single-cell RNA sequencing, high end imaging and multiparametric flow cytometry, to characterize the transplanted macrophages and their interaction with other cells at different stages of MASLD. Our work will thoroughly characterize the phenotype and mode of action of transplanted macrophages within the inflamed and fibrotic hepatic microenvironment, and hence their therapeutic potential in MASLD.

PIs: Michael Sieweke / Efstathios Stamatiades

Sensing hepatic cellular stress is a central event in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the role of lymphocyte innate sensors in mediating this process remains unclear. By using a combination of multi-omics analyses along with genetic mouse models, we will assess the molecular mechanisms driving the upregulation of stress ligands, define the function of lymphocyte innate sensors and evaluate their impact on modulating MASLD. Our findings will provide a comprehensive picture of how lymphocyte sensors contribute to MASLD inflammation and progression and how this might provide novel opportunities for therapeutic interventions.

PIs: Christina Stehle / Chiara Romagnani

Innate lymphoid cells (ILC) are involved in tissue homeostasis. Their activity is modulated by microbiota and nutrients. ILC3-derived IL-22 acts on hepatocytes and plays an important role in liver regeneration, while the roles of ILC3 and IL-22 in MASLD remain poorly studied. Using state-of-the-art in vivo models and gnotobiology techniques, we will explore how intestinal microbiota impacts on hepatic and intestinal ILC3 and on the role of IL-22 in regulating hepatocyte function, during MASLD and disease regression. Our results will reveal molecular pathways of how ILC3 and IL-22 control tissue recovery from MASLD in a diet-microbiota dependent manner and might become targets for novel therapies.

PIs: Francesca Ronchi / Andreas Diefenbach

Hepatic-MBOAT7 downregulation in obese humans and mice is associated with the development of liver fibrosis. We hypothesise that bioactive lipids secreted by MBOAT7-deficient hepatocytes mediate pro-fibrotic crosstalk with hepatic stellate cells (HSCs) via specific lipid signaling pathways. Using in vitro experiments with mouse/human primary cells and mass spectrometry based lipidomics we will identify molecular players of the proposed signaling mechanism and validate it in vivo using various transgenic mouse models and pharmacological inhibitors. Our findings will identify druggable pathways that drive the MBOAT7-dependent cellular crosstalk and fibrosis.

PIs:  Vasileia Ismini Alexaki   / Maria Fedorova

 In metabolic dysfunction-associated steatotic liver disease (MASLD), the two critical steps of progression from steatosis to metabolic dysfunction-associated steatohepatitis (MASH) are (i) the onset of inflammation and (ii) the development of liver fibrosis. Furthermore, the inflammatory state of MASH is paradoxically accompanied by the suppression of innate and adaptive immunity in advanced stages, contributing to infection-related complications. Hepatic stellate cells (HSCs) represent the primary source of ECM deposition driving the fibrotic remodeling of the liver. Kupffer cells (KCs), the tissue-resident liver macrophages, critically mediate the switch from “benign” steatosis to inflammation. KCs and HSCs, thus are at the root of (i) the onset of inflammation and (ii) fibrogenesis, making these cells intriguing targets of therapeutic intervention.  

B09 tests the hypothesis that HSC-KC crosstalk controls the homeostatic and tolerogenic immune milieu of the liver. Altered niche signals from HSCs could hence lead to spatial and phenotypical uncoupling of HSCs and KCs in MASLD, a phenotype loss of KCs and the recruitment of ontogenically distinct macrophages, thereby causing inflammation and MASLD progression. Therapeutic restoration of the homeostatic HSC-KC circuits in advanced MASLD and fibrosis may promote disease resolution and fibrosis regression.  

PI: Moritz Peiseler