Newly discovered metabolic mechanism could be an off-switch for inflammation
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 systemresponse to help the body protect itself from harmful external stimuli. Butsometimes inflammation can flare up out of control and result in a number ofdiseases, from simple allergies to more complex gastrointestinaldisorders. Inflammation has also recently been suspected to be connectedto everything from cancer to depression.
The best treatment we have today for anacute inflammatory flare-up is still an old-fashioned steroidalimmunosuppressive drug. These drugs can sometimes have significant negative side-effects and stifle the immune system to such an degree that it makes the patient highly susceptible to other infections.
Now a team at Trinity College Dublin has found that "itaconate" – amolecule derived from glucose – may act as an off-switch formacrophages, one of the immune cells responsible for inflammatory responses.
"My lab has been exploring metabolicchanges in macrophages for the past six years and we've come acrosswhat we think is the most important finding yet," explains LukeO'Neill, joint leader in the research at Trinity. "It is wellknown that macrophages cause inflammation, but we have just foundthat they can be coaxed to make a biochemical called itaconate. Thisfunctions as an important brake, or off-switch, on the macrophage,cooling the heat of inflammation in a process never beforedescribed."
Research into itaconate is very much inits early stages, and while other recent studies have revealed thecompound to be an important regulator of macrophage function, verylittle has been known about how it actually works. This new studyoffers a vital insight into how macrophages could be manipulated toreduce the levels of inflammation they produce.
"The macrophage takes the nutrientglucose, whose day job it is to provide energy, and surprisinglyturns it into itaconate," says Dylan Ryan, joint first author on the new study. "This then blocks production of inflammatoryfactors, and also protects mice from the lethal inflammation that canoccur during infection. We've found that itaconate can directly modify awhole host of proteins important for inflammation in a chemicalreaction never before described, and that this reaction is importantfor the anti-inflammatory effects of itaconate."
The researchers are investigatingseveral pathways for future study. As well as examining how thisnewly revealed mechanism could play a part in the onset ofinflammatory diseases, it hopefully could lead to the development ofnew anti-inflammatory drugs that could treat everything frominflammatory bowel disease to arthritis.
The study was published in the journal Nature.
Source: Trinity College Dublin