Pilot Project Awarded 2016
The Role of CerS6 in Colitis
The balance between inflammatory IL-17 secreting T cells and suppressive T regulatory cells is critical for maintaining immune homeostasis. A key difference between these T cell subsets with opposing function is their energy metabolism. Inflammatory T cells use the glycolyticlipogenic pathway, whereas suppressive T regulatory cells rely on mitochondrial fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC1) functions as a central switch between these metabolic pathways. We hypothesize that CerS6-deficiency leads to an accumulation of its substrate palmitoyl-CoA resulting in compensatory upregulation of FAO and/or inhibition of ACC1. Increased utilization of lipids in the liver and adipose tissue in CerS6 KO mice supports this hypothesis. We further predict that the consequence of this key metabolic difference is the preferential development of suppressive T regulatory cells. Our preliminary data suggest that CerS6 KO mice are more tolerant to colitis and have fewer splenic inflammatory CD8 T cells, which is consistent with a subdued inflammatory response. Our long-term goal is to understand the influence of sphingolipid metabolism on the immune system, which would lay the foundation for the development of novel therapeutic strategies for immune disorders.