Can this biochemical 'switch off' inflammation?

Macrophages are cells that play a key role in inflammation. And now, new research — led by Trinity College Dublin in Ireland — has found a previously unknown process that can switch off the production of inflammatory factors in macrophages.

The researchers suggest that the new discovery improves our understanding of inflammation and infection.

They hope that it will lead to new treatments for inflammatory diseases such as heart disease, rheumatoid arthritis, and inflammatory bowel disease.

Their recent discovery concerns a molecule known as itaconate, which macrophages produce from glucose.

Previous studies had already shown that the molecule helps to regulate macrophage function, but precisely how it did so was unclear.

"It is well known," explains co-senior study author Luke O'Neill, a professor of biochemistry from Trinity College Dublin, "that macrophages cause inflammation, but we have just found that they can be coaxed to make a biochemical called itaconate."

Using human cells and mouse models, he and his colleagues found that the production of itaconate was similar to activating an "off-switch, on the macrophage, cooling the heat of inflammation in a process never before described."

The researchers report their findings in a paper now published in the journal Nature.

Inflammation and macrophages

Inflammation is a series of biochemical responses launched by the immune system when it detects something that might cause harm. We can see and feel it when we get a splinter in our finger, for example; the wound area swells, reddens, throbs, and becomes painful.

As the process of inflammation unfolds, groups of different cells release substances that, in turn, trigger a range of responses.

For example, they cause blood vessels to expand and become permeable so that more blood and defense cells can reach the site of injury, and they irritate nerves so that pain messages travel to the brain.

However, this powerful defense system can also be triggered when the immune system attacks healthy cells and tissue by mistake. This gives rise to inflammatory diseases that can last for many years — sometimes even a lifetime.

Macrophages are diverse cells that are involved in many important processes in the body, including inflammation.

Their name comes from the Greek for "big eaters," because they ingest and process dead cells, debris, and foreign materials.

Itaconate and type I interferons

Like many cells, macrophages use glucose for energy. However, they can also be induced to use it to produce itaconate. Scientists already knew that itaconate helps to regulate many cell processes in macrophages, but the biochemistry involved was not clear.

In the new study, Prof. O'Neill and colleagues showed, for the first time, that "itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 [...] in mouse and human macrophages."

They demonstrated how, by altering the production of several inflammatory proteins, itaconate protected mice from a type of deadly inflammation that can arise during infection.

One of the effects of itaconate production was to limit an inflammatory response involving type I interferons.

Type I interferons are a group of proteins that influence immune responses that arise during infection by viruses, bacteria, fungi, and other pathogens.

The proteins are known to be particularly important for defending against viruses. However, they can also cause undesirable reactions in some types of infection.

The authors conclude that their findings "demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons."

In being the first to describe the chemical reactions behind itaconate's anti-inflammatory effects, the study represents pioneering work in the field of inflammation research.

The researchers now plan to find out how to make use of the findings to make new anti-inflammatory drugs.

"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."

Prof. Luke O'Neill

In addition to the researchers from Trinity College Dublin, scientists from the following institutions also collaborated: Harvard Medical School in Boston, MA; Johns Hopkins University in Baltimore, MD; the University of Cambridge, the University of Oxford, and the University of Dundee, all of which are in the United Kingdom; and the pharmaceutical company GlaxoSmithKline.