Researchers at Trinity College Dublin have uncovered a new metabolic process involved in the immune system's inflammatory processes. The discovery suggests manipulating this mechanism could essentially "switch off" inflammation, which the researchers hope could lead to the development of entirely new anti-inflammatory drugs to treat a host of auto-immune disorders.

When the body is working properly, inflammation is a good thing. It is our natural immune system response to help the body protect itself from harmful external stimuli. But sometimes inflammation can flare up out of control and result in a number of diseases, from simple allergies to more complex gastrointestinal disorders. Inflammation has also recently been suspected to be connected to everything from cancer to depression.

The best treatment we have today for an acute inflammatory flare-up is still an old-fashioned steroidal immunosuppressive drug. These drugs can sometimes have significant negative side-effects and stifle the immune system to such a degree that it makes the patient highly susceptible to other infections.

Now a team at Trinity College Dublin has found that "itaconate" – a molecule derived from glucose – may act as an off-switch for macrophages, one of the immune cells responsible for inflammatory responses.

"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," explains LukeO'Neill, joint leader in the research at Trinity. "It is well known that macrophages cause inflammation, but we have just found that 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."

Research into itaconate is very much inits early stages, and while other recent studies have revealed the compound to be an important regulator of macrophage function, very little has been known about how it actually works. This new study offers a vital insight into how macrophages could be manipulated to reduce the levels of inflammation they produce.

"The macrophage takes the nutrient glucose, whose day job it is to provide energy, and surprisingly turns it into itaconate," says Dylan Ryan, joint first author on the new study. "This then blocks production of inflammatory factors, and also protects mice from the lethal inflammation that can occur during infection. 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 researchers are investigating several pathways for future study. As well as examining how this newly revealed mechanism could play a part in the onset of inflammatory diseases, it hopefully could lead to the development of new anti-inflammatory drugs that could treat everything from inflammatory bowel disease to arthritis.

The study was published in the journal Nature.

Source: Trinity College Dublin

