DC 10 - Lipid Metabolism and Organ Cross-Talk in Granulomatous Inflammation

• Objectives:

Aim of the project: To define how lipid metabolic pathways, particularly CYP27A1-driven oxysterol metabolism, shapes macrophage metabolic and functional programming in granulomatous inflammation and tumor immunity.

1. analyze the metabolic and lipidomic profiles of macrophages in vitro and ex vivo following manipulation of Cyp27a1.;
2. explore how local and systemic lipid metabolism controls macrophage differentiation and effector functions in granuloma models;
3. investigate the role of local and systemic Cyp27a1 in the tumor microenvironment using MC38 and B16-F10 tumor models;
4. Assess the relevance of identified lipid pathways in granulomatous and tumor disease using sarcoidosis or melanoma patient samples and multi-omics datasets.

• Brief project description:

Tissue macrophages (TMs) are essential regulators of tissue homeostasis and immune responses. Their ability to integrate local and systemic metabolic cues enables them to maintain core functions while adapting to pathological challenges (1). Among these cues, lipid and cholesterol metabolism are central drivers of macrophage differentiation, metabolic programming, and inflammatory activation. One key pathway involves oxysterol metabolism via the enzyme CYP27A1, which influences redox balance, nucleotide synthesis, and communication between organs and immune cells.

The precise role of lipid metabolism in shaping macrophage behavior within complex tissue environments such as granulomas or tumors, and how these pathways contribute to systemic metabolic and immune regulation, remains poorly understood (2). Recent work from our laboratory shows that macrophage-specific loss of Cyp27a1 reshapes intracellular metabolite pools and regulates granulomatous inflammation as well as tumor immunity, pointing to a previously unrecognized link between macrophage Cyp27a1-dependent metabolism and immune control.

• Planned secondments:

Luciana Berod lab (University Medical Center of Mainz, Germany)
• Learn lipidomics and transcriptomics analysis of macrophages

Vugene, Dr. Marina Makrecka-Kuka, (Vugene, Lithuania)
• Analyze lipidomics data and perform integrated analyses of sequencing and multi-omics data.