Project Details
Projekt
Lipogranuloma formation in steatohepatitis
Applicants
Dr. Cristina Cadenas; Professor Dr. Jan G. Hengstler
Subject Area
Gastroenterology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894
Monocyte/macrophage infiltration is a critical step occurring during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic-dysfunction-associated steatohepatitis (MASH) leading to the formation of lipogranulomas that appear as “macrophage crowns” where macrophages surround large lipid droplets. However, it remains unknown, which key features of lipid droplets, such as large size or chemical composition cause the infiltration of macrophages and crown formation, and which mechanisms are responsible for this process. Therefore, project P05 aims to clarify the causal relationships during the process of lipogranuloma formation and its consequences, with a focus on release and effector mechanisms of DAMPs. Specifically, the following four objectives will be addressed: (i) defining the time course of DAMP release and macrophage infiltration by intravital imaging; (ii) identifying the key stimuli causing DAMP release from steatotic hepatocytes; (3) understanding the fate and consequences of macrophage crowns; (iv) understanding the translational/human relevance of the experiments in mice and in vitro. Project P05 is centrally embedded within the dangerhep consortium on both a conceptual level where we will collaborate with P01-P03 based on our recent discovery of sublethal necroptosis and DAMP release, the reversibility of immune cell infiltration in MASH (P08, P09) and the role of sphingolipids, autophagy and peripheral fat, since macrophage crowns are also formed in fat tissue (P04-P07). We (P05) will contribute MALDI-MSI and techniques for the characterization of DAMPs to the general toolbox and will make use of 2-photon microscopy (C01), lipidomics (P07), immunophenotyping (P08, P09), deep learning (P01), the HMGB1 reporter mice (P02), and the biobank (P08). By integrating project P05 into the dangerhep project, conceptual and methodological synergies will be enabled that will significantly advance our understanding of how lipogranulomas are formed and how they drive stage transitions to more severe inflammation, cirrhosis and HCC. If these mechanisms are relevant for patients, their understanding may lead to interventions that ameliorate DAMP release and chronic inflammation.
DFG Programme
Research Units
