The influence of lipidome alterations on dendritic cell functionality in fatty liver (MASLD)

Principle Investigator

Scientific interest within the context of the graduate college:

Our lab studies the role of immune cells and inflammatory processes in the liver. During homeostasis the liver plays an important role in adaptation to environmental influences as it is constantly exposed to antigens from the gastrointestinal system, and plays a critical role in maintaining a balance between tolerance to harmless antigens (eg. food proteins or commensal bacteria) and control of pathogens.¹ When this balance is disrupted (termed maladaptation) the resulting immune-mediated changes can lead to chronic liver diseases and ultimately cancer.² Infiltration and activation of immune cells play an important role during the development of liver diseases, but the exact molecular and cellular mechanisms leading to the development of liver inflammation have not been fully elucidated until now. We are exploring the inflammatory processes during acute liver failure, metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH), liver cirrhosis and liver cancer in order to develop new diagnostic and therapeutic strategies. Furthermore, a better understanding of how both pro- and anti-inflammatory pathways can disrupt the homeostatic processes of a healthy liver is critical for the prevention of liver diseases in the first place.

Project description:

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, affecting a staggering 30% of the general population, and its prevalence is expected to rise further with an aging and more obese world population. MASLD is characterized by persistent inflammation and subsequent liver fibrosis, which can progress to steatohepatitis, cirrhosis and cancer. Dendritic cells (DC) have been shown to accumulate in chronic liver diseases, but their exact role in liver inflammation and fibrosis is complex and incompletely understood. In the context of MASLD/MASH, specific DC subsets correlate with disease severity in patients and drive liver pathology in mouse models.³ Furthermore, it has been shown that the lipid content of DC can significantly influence their functionality, with “lipid-high” DC displaying a proinflammatory phenotype while “lipid-low” DC seem to be rather tolerogenic.⁴ In this project, we would like to study how changes in the hepatic lipidome influence infiltration, differentiation and function of DCs and how this could be targeted to prevent or reverse the development of MASLD. For this purpose, tissue samples from both patients and mice with MASLD/MASH will be analyzed with state-of-the-art single-cell technologies, such as full spectrum flow cytometry,⁵ imaging mass cytometry and mass spectrometry imaging.⁶ This will be complemented by functional in vitro and ex vivo experiments using 2D and 3D cell culture systems.

Aim 1: Characterize the relationship between the hepatic lipidome and dendritic cell subsets in MASLD. Human and murine liver samples will be analyzed by imaging to mass cytometry to determine infiltration patterns of DC subsets and mass spectrometry imaging to characterize the hepatic lipid environment(s). Correlation of the results will determine which lipid species are associated with DC infiltration and distribution in the tissue.

Aim 2: Understand the influence of lipid species on dendritic cell differentiation and maturation in vitro. In vitro culture of primary human and murine dendritic cells with lipid species identified in Aim 1 will be used to analyze their influence on DC differentiation, activation and maturation. Readouts will include full spectrum flow cytometry, cytokine measurements as well as functional assays (e.g. antigen presentation).

Aim 3: Modulate dendritic cell functionality in vivo. Human and mouse hepatic organoids will be used to test how DC function can be targeted to prevent differentiation into pathogenic phenotypes, eg. through inhibition of uptake of certain lipid species and/or reprogramming of intracellular DC lipid metabolism.

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