Session 2

Luke O’Neill

A break in endosymbiosis as a basis for inflammatory diseases

School of Biochemistry and Immunology, at Trinity College Dublin, Ireland

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 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 are therefore acting as signals and impacting on signalling pathways in unexpected ways. Changes in Krebs cycle and the Electon transport chain also play a role in tumorigenesis and we also have data on a role ROS from Complex III in driving immunosuppressive IL10 in melanoma. These insights are providing a new view of metabolism in immunity and inflammation and might indicate new therapeutic approaches.

Douglas Golenbock

UMass Chan Medical School, Worcester, Massachusetts, USA

Andreas Ablasser

Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland

Gunther Hartmann

Institute of Clinical Chemistry and Clinical Pharmacology with Central Laboratory, University Hospital Bonn, Germany