Professor Luke O'Neill; School of Biochemistry and Immunology, Trinity College Dublin

Title: How a break in mitochondrial endosymbiosis might lie at the heart of inflammatory diseases

Biography:

Luke O’Neill’s research investigates the mechanistic basis for inflammatory diseases. He obtained a PhD in Pharmacology from the Royal College of Surgeons in 1988, working on cytokines and prostaglandins. He then carried out post-doctoral work at the Strangeways Research Laboratory in Cambridge on the cytokines TNF and IL-1. He has led a research team in Trinity College Dublin for over 30years, making numerous contributions to the field of innate immunity and inflammation. His pioneering work on innate immunity, specifically on Toll-like receptors and the NLRP3 inflammasome has been used in both big pharma and biotech in their efforts to discover therapeutics for a range of autoimmune and inflammatory diseases. His discovery of the NLRP3 inhibitor CRID3/MCC950 led to his company Inflazome discovering potent and safe NLRP3 inhibitors which were acquired by Roche Ltd and are now in clinical trials for severe asthma, Parkinson’s disease and heart disease. This discovery spurred others and at least 9 NLRP3 inhibitors are at various stages of clinical development. He is also a key scientist in the field of immunometabolism which led to the founding of Sitryx Ltd which has developed 2 lead compounds based on his work, one of which has already entered the clinic for inflammatory diseases. He is listed by Thompson Reuters/ Clarivates in the top 1% of immunologists in the world, based on citations per paper. He has won numerous awards for his research notably the Royal Dublin Society Boyle Medal for scientific excellence, the Royal Irish Academy Gold Medal for Life Sciences, The Society for Leukocyte Biology (SLB) Dolph O. Adams award, the European Federation of Immunology Societies Medal, and the Milstein Award of the International Cytokine. He is a member of the Royal Irish Academy, EMBO) and a Fellow of the Royal Society.

Abstract:

Metabolic changes triggered during innate immunity have become a particular focus for researchers interested in inflammation, whilst cancer researchers have had a long standing interest in metabolic disturbance since the days of Warburg. Mitochondrial disturbance is a feature of inflammatory cells and we have been analysing the Krebs cycle intermediates succinate and fumarate, as well as the Krebs cycle-derived metabolite itaconate, in activated macrophages in response to signalling by Toll-like receptors. Itaconate derivatives are anti-inflammatory and have potential for the treatment of immune and inflammatory diseases. Fumarate is proving to be a very interesting metabolite. It is generated via repression of the enzyme FH and also induction of the argininosuccinate shunt. Fumarate suppresses IL10 production which in turn leads to increased TNF. The decrease in FH and also inhibition of Succinate Dehydrogenase(SDH) by itaconate however also leads to mitochondrial disturbance, which involves release of double-stranded mitochondrial RNA. This is sensed by the RNA sensors RIG-I, MDA-5 and TLR-7 driving production of Type I Interferons. Metabolites like fumarate and itaconateare therefore acting as signals and impacting on signalling pathways in unexpected ways. Overall evidence is growing that a break inmitochondrial endosymbiosis might be a reason for the increasing indcidence of autoimmune and inflammatory diseases. These insights are providing a new view of metabolism in immunity and inflammation and might indicate new therapeutic approaches.

Babraham Distinguished Lecture - Professor Luke O'Neill