Scientists Discover Switch that could “Turn Off” Inflammation
The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood.
However, researchers at the Trinity College Dublin have now discovered that this molecule acts as a powerful off-switch for macrophages, which are the cells in the immune system that lie at the heart of many inflammatory diseases including arthritis, inflammatory bowel disease and heart disease.
Professor of Biochemistry at Trinity, Luke O’Neill, co-author of the study, said, “My lab has been exploring metabolic changes in macrophages for the past six years and we’ve come across what we think is the most important finding yet.”
Macrophages are a type of white blood cell which digest cellular debris; foreign substances, microbes, cancer cells, and anything else that does not have the type of proteins specific to a healthy body. When operating optimally they respond rapidly to pathogens and trigger anti-inflammatory activity. That in turn limits damage and promotes tissue repair.
Normally, inflammation is a good thing as, for example, with a sprained ankle and accelerates recovery. But with specific inflammatory diseases such as multiple sclerosis, psteoarthritis and the inflammatory skin disorder psoriasis
, macrophages act mischievously, Prof O’Neill said. “We don’t know why inflammation goes out of control.”A critical finding was to show itaconate switched off an over-active immune system in mice.
“It’s well known that macrophages cause inflammation, but we have just found they can be coaxed to make a biochemical called itaconate. This functions as an important brake, or off switch, on the macrophage, cooling the heat of inflammation in a process never before described,” Prof O’Neill said.
Dr Evanna Mills, who, with Dylan Ryan was joint first author of the work, said: “The macrophage takes the nutrient glucose, whose day job it is to provide energy, and surprisingly turns it into itaconate. This then blocks production of inflammatory factors, and also protects mice from the lethal inflammation that can occur during infection.”
Dylan Ryan added: “We’ve found that itaconate can directly modify a whole host of proteins important for inflammation in a chemical reaction never before described, and that this reaction is important for the anti-inflammatory effects of itaconate.”
The discovery is very much on the frontier of inflammation research and Professor O’Neill and his collaborators are now exploring its relevance to the onset and development of inflammatory and infectious diseases. They are also keen to explore whether the findings can be exploited in the effort to develop new anti-inflammatory medicines.
Professor O’Neill said: “This discovery and the new research pathways it has opened up will keep us busy for some time but we are hopeful that it will one day make a difference to patients with diseases that remain difficult to treat.”
