Metabolic reprogramming in innate immunity

Professor O’Neill will investigate metabolic changes occurring in macrophages upon activation of innate immune signalling pathways. Metabolic reprogramming of cells of the immune system has been the focus of recent work by immunologists, with complex alterations occurring in metabolic pathways that govern the function of the immune cell being activated. Specific metabolites accumulate, that then signal to gene expression programmes, enhancing immunity and inflammation. Firstly, the role of the metabolite succinate in generating reactive oxygen species from complex I in reverse electron transport will be investigated. Citrate accumulation leading to the production of malonyl-CoA and malonylation of the enzyme GAPDH will then be examined in detail. This process might lead to GAPDH dissociating from target mRNAs for critical inflammatory mediators, leading to enhanced translation. Finally, the role of glutathionylation and its regulation by the enzyme glutathione transferase omega will be further analysed, as this appears to be another determining event in macrophage activation. This project may point to new therapeutic approaches to limit macrophages in inflammatory and immune diseases.