Presentation: Targeting Immunometabolism to Treat Inflammatory Diseases

Metabolic reprogramming is a feature of inflammatory cells, and we have been analysing mitochondrial metabolites, notably itaconate and fumarate in inflammatory macrophages. Itaconate derivatives are anti-inflammatory and have potential for the treatment of immune and inflammatory diseases, including rheumatoid and osteoarthritis. 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 lead 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. FH and fumarate have been analysed in patients with SLE and Systemic Sclerosis, with FH repression being a possibly pathologic event. Metabolites like fumarate and itaconate are therefore acting as signals for cytokine production.

In addition, we have bene exploring the role of Complex III in the electron transport chain in IL-10 production, and the role of IL10 as a mitochondrial stabiliser, it’s production being driven by the glycolytic enzyme PKM2 via adenosine. We also have evidence that the mitochondrial glutathione transporter SLC25A40 is required for inflammatory cytokine production.

Overall evidence is growing that a break in mitochondrial endosymbiosis might be a reason for the increasing incidence of autoimmune and inflammatory diseases. These insights are providing a new view of metabolism in immunity and inflammation and might indicate new therapeutic approaches.