Periodic Reporting for period 1 - Metabo3DC (Understanding Metabolic Activation of Dendritic Cells in Non-Alcoholic Fatty Liver Disease)
Reporting period: 2022-09-01 to 2025-02-28
Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) has emerged as a pressing global health challenge, affecting a nearly 30% of adults worldwide and with limited therapeutic options. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), is particularly concerning due to its association with severe comorbidities including hepatocellular carcinoma, cardiovascular disease, and type 2 diabetes. The Metabo3DC project focuses on identifying the immunological mechanisms linking metabolic disturbances to disease progression to MASH. This project addresses this critical knowledge gap by focusing on conventional dendritic cells (cDC), which coordinate innate and adaptive immune responses, and whose role in MASH pathogenesis is underexplored. The core objective is to dissect the impact of the hepatic immune-metabolic environment impacts the transiting cDC during MASLD development and resolution. We aim to achieve this first by profiling these cells across the spectrum of MASLD severity and post MASLD resolution, with the goal of identifying disease-associated cDC subtypes, understanding their metabolic regulation, and testing how targeted metabolic interventions can alter disease outcomes. We will then use the markers identified to study how specific cDC phenotypes relate to hepatocyte damage and specific metabolic environments in the liver. By investigating the interplay between local liver metabolism and immune cell function, this project has the potential to redefine our understanding of MASH and open new avenues for targeted immunometabolic therapies. The multidisciplinary approach, integrating immunology, metabolism, and liver pathology, positions this work to make a significant impact on both the scientific understanding of chronic liver disease and the development of novel therapeutic strategies.
Major progress has been made on WP1 of the project essentially as described in the proposal. We have identified a hepatic cDC population that is highly enriched in livers affected by MASH in our mouse model. Interestingly, we found this cDC sub population has a specific metabolic phenotype related to cholesterol metabolism. We have been testing methods of altering cholesterol metabolism in vitro to understand the role of this metabolic pathway in the function of the DC population enriched in MASH livers as outlined in WP2. In parallel, we have been working toward developing mutiplex immunflorescence methods in human samples to determine where the MASH-specific cDC population is localized in the liver and if we can determine other immune cells that are close by. These results have helped advance our understanding of the metabolic factors that drive the breakdown of immune homeostasis in MASH.
By the end of the project, we anticipate generating several key results that will significantly advance the understanding of MASH pathophysiology. One of the major adverse outcomes associated with MASH in humans is progression to cancer (either hepatocellular carcinoma or extrahepatic cancers). Interestingly, the dendritic cell phenotype we identified as enriched in MASH very closely mirrors a signature described for cDC in the tumor microenvironment. Collectively, these findings may lead to novel immunometabolic targets that could be exploited for therapeutic intervention, both for MASH and perhaps hepatocellular carcinoma — both of which have a significant unmet clinical need. My team has also participated in efforts to better stratify risks for patients with MASLD (Raverdy et al. Nature Medicine 2024). Together with our experimental work, this project will contribute to the development of precision medicine based therapeutic strategies.
To enable further uptake and long-term success, several needs must be addressed. Continued research will be essential to validate the identified mechanisms and targets in broader patient populations and to explore their therapeutic modulation in preclinical models. Engagement with pharmaceutical partners and translational researchers will be critical for the design of drug development or repurposing strategies. Additionally, support for intellectual property (IPR), access to innovation funding, and eventual commercialisation pathways will be important for moving discoveries from the bench to the bedside.
To enable further uptake and long-term success, several needs must be addressed. Continued research will be essential to validate the identified mechanisms and targets in broader patient populations and to explore their therapeutic modulation in preclinical models. Engagement with pharmaceutical partners and translational researchers will be critical for the design of drug development or repurposing strategies. Additionally, support for intellectual property (IPR), access to innovation funding, and eventual commercialisation pathways will be important for moving discoveries from the bench to the bedside.