DC 12 - The role of lipid metabolism in shaping dendritic cell tolerogenic properties

• Objectives:

Aim of the project: Unravel how gut environmental cues impinge on AMPK to shape lipid catabolism and the tolerogenic properties of intestinal DCs. This can potentially open avenues for developing novel metabolism-based approaches to promote tolerogenic responses in the fight against inflammatory diseases such as IBD.

1. characterize the metabolic properties of tissue-specific dendritic cell subsets with a focus on lipid metabolism and define the role of the nutrient sensor AMPK herein;
2. identify tissue-specific signals that influence AMPK activation and lipid metabolic profiles in dendritic cells;
3. test how alterations of dendritic cell AMPK (using AMPKα1-ΔDC mice) signalling and lipid metabolism affect gut tolerance during steady state and colitis-associated inflammation.

• Brief project description:

Dendritic cells (DCs) control the balance between immunity and tolerance by governing effector and regulatory T cell (Treg) responses, respectively. The latter property is fundamental in the intestine, where maintenance of immune tolerance by DCs is crucial to prevent overt inflammation that could otherwise lead to inflammatory disorders, such as inflammatory bowel disease (IBD). We have identified the nutrient sensor AMPK as a key regulator of DC-driven tolerance. However, the in vivo and translational relevance of these findings remains unknown. Specifically, what signals in the microenvironment promote AMPK activation in gut DCs, how this is linked to their lipid metabolic and tolerogenic profile, and whether this AMPK/lipid catabolism axis in gut DCs can be targeted to shape intestinal tolerance are still unanswered questions.

• Planned secondments:

Biocrates lab (Viena, Austria)
• Get trained in performing metabolomics on tissue fluids.

Brenner lab (Luxembourg Institute of Health, Luxembourg)
• Perform metabolite screens on DCs to evaluate their effects on DC AMPK activation and lipid metabolism.