Metabolic crosstalk in the regulation of inflammation

ended

The study of the molecular basis to the immune response has for decades concerned receptors and the signalling pathways they activate which lead to immune cell activation. Recently metabolic changes have also been shown to couple to immune effector responses. A shift in appreciation of the role of metabolites beyond energy metabolism and biosynthetic processes has emerged. We have been examining the role of three metabolites in macrophages. We have evidence that two of these, malonyl-CoA and 2-hydroxyglutarate (2-HG) are pro-inflammatory, whilst the third, itaconate, has profound anti-inflammatory effects. In many ways, they mirror cytokines, with malonyl-CoA and 2-HG being akin to pro-inflammatory cytokines, whilst itaconate resembles anti-inflammatory cytokines. The specificity and breadth of the role of these metabolites in macrophages will be mapped in this proposal. For malonyl-CoA we have evidence that it regulates GAPDH, IRG1/CAD (which synthesises itaconate) and the key cytokine IL-1beta. For 2-HG, we will examine the production and actions of its 2 enantiomers, D-2-HG and L-2-HG, focusing on their effect on HIF1alpha and epigenetic regulation. For itaconate we have evidence for a role in Type I interferon modulation, antigen presentation, inflammasome regulation and GAPDH and LDHA (which can produce 2-HG) activities. We also have evidence that OXGR1 is the receptor for itaconate. All of these aspects will be explored in detail. Critically we will also determine the relationship between these metabolites since we have evidence for cross-talk. Their dynamic regulation is likely to be a key aspect of how metabolic reprogramming controls macrophage function. Our studies point to a major shift in our understanding of how intracellular metabolic changes lead to inflammation. The overall aim is therefore to elucidate how metabolic reprogramming controls inflammatory macrophage activation, which may lead to new therapeutic targets for inflammatory diseases.