Luke A. O’Neill
Luke O’Neill is Professor of Biochemistry (Inflammation Research) in the School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland. His research aims to provide a molecular understanding of innate immunity and inflammation, specifically the receptors involved in innate immunity, such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs, including Nlrp3), and signals activated. The role played by this system in inflammatory diseases is also under investigation. Ultimately, insights from this research may help in the design of novel treatments and diagnostics that could be applied to a range of diseases including atherosclerosis, sepsis, arthritis and cancer.
Monday 27 May 09:00
Macrophage immunometabolism: opportunities for phenotypical modulation?
Macrophages play a key role in atherosclerosis, from initiation of atherogenesis to ultimate plaque rupture. In the atherosclerotic plaque microenvironment, macrophages are exposed to a variety of chemical influences, including proinflammatory cytokines, oxidized lipids, cholesterol crystals and oxidative stress biomarkers, which together influence macrophage phenotype and perpetuate inflammation. Recent studies have shown that glucose, cholesterol, fatty acids, and amino acids have the ability to re-programme macrophage metabolism and thus influence inflammatory responses. There is also evidence that epigenetic and metabolic memory can play a role. For example, macrophages exposed to acute or chronic stimuli exhibit innate immune memory, characterized phenotypically by cellular inflammatory responses that are partly regulated by changes in metabolic programming. These metabolic changes are likely to be dynamic, because the microenvironment evolves during plaque progression and treatment of disease.
Increased understanding of macrophage immunometabolism has led to interest into the therapeutic potential for modulation of the inflammatory phenotype of plaque macrophages. Insights into the processes that underpin maladaptive changes in macrophage metabolism during atherosclerosis can help to identify novel targets, either metabolic intermediates or pathways, that are critical to rebalancing inflammatory responses and restoring protective immune function. Such insights could lead to the development of small molecule therapeutic approaches that are able to ‘re-programme’ aberrant macrophage responses and ultimately restore homeostasis in the artery wall.
Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, Jedrychowski MP, Costa ASH, Higgins M, Hams E, Szpyt J, Runtsch MC, King MS, McGouran JF, Fischer R, Kessler BM, McGettrick AF, Hughes MM, Carroll RG, Booty LM, Knatko EV, Meakin PJ, Ashford MLJ, Modis LK, Brunori G, Sévin DC, Fallon PG, Caldwell ST, Kunji ERS, Chouchani ET, Frezza C, Dinkova-Kostova AT, Hartley RC, Murphy MP, O’Neill LA. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 2018;556:113-7.
Carroll RG, Zasłona Z, Galván-Peña S, Koppe EL, Sévin DC, Angiari S, Triantafilou M, Triantafilou K, Modis LK, O’Neill LA. An unexpected link between fatty acid synthase and cholesterol synthesis in proinflammatory macrophage activation. J Biol Chem 2018;293:5509-21.
Hughes MM, O’Neill LA. Metabolic regulation of NLRP3. Immunol Rev 2018;281:88-98.