Scientists discover promising ‘off-switch’ for inflammatory diseases

Trinity College researchers play leading role in breakthrough discovery

 

Scientists in Ireland, the UK and US have discovered a new metabolic process in the body that can switch off inflammation. The discovery opens up a strong possibility of more effective treatment of inflammatory diseases such as arthritis, inflammatory bowel disease and heart disease.

Researchers based at the Biomedical Sciences Institute at Trinity College Dublin, who played a leading role in the breakthrough, hope the discovery will lead to much-needed new drugs to treat people living with inflammatory and infectious diseases by switching off over-active immune cells which arise with these conditions.

Teams led by immunologist Prof Luke O’Neill, who is based in Trinity, and Dr Mike Murphy, of the University of Cambridge, have discovered that “itaconate” – a molecule derived from glucose – “acts as a powerful off switch for macrophages”, which are cells operating at the heart of the the immune system where inflammation occurs.

“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,” said Prof O’Neill.

Their work is published in the latest issue of leading international journal Nature, and follows discoveries made using both human cells and mice as a model organism.

Cellular debris

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, osteoarthritis 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.

Itaconate

Dr Evanna Mills, who with PhD student Dylan Ryan is the 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.”

Prof O’Neill and his collaborators are 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.

The work was a collaboration with the University of Cambridge; Harvard Medical School; the University of Oxford, Johns Hopkins University, the University of Dundee, and the pharmaceutical company GlaxoSmithKline.

The work was funded by the Wellcome Trust, Science Foundation Ireland, the European Research Council and GSK.