Researchers at University College London (UCL) have uncovered a key mechanism that helps the body switch off inflammation – a breakthrough that could lead to new treatments for chronic diseases affecting millions worldwide.
Inflammation is the body's frontline defence against infection and injury, but when it doesn't switch off properly, it can drive serious health conditions such as arthritis, heart disease, and diabetes. Until now, scientists didn't fully understand how the body decides to stop the immune 'fight' response and start healing.
Published in Nature Communications, the study reveals that tiny fat-derived molecules called epoxy-oxylipins act as natural brakes on the immune system. These molecules prevent the overgrowth of certain immune cells, known as intermediate monocytes*, that can cause chronic inflammation – linked to tissue damage, illness and disease progression.
For the study, healthy human volunteers were given a tiny injection of UV-killed E. coli bacteria into the forearm, which triggered a short-lived inflammatory reaction – pain, redness, heat and swelling – similar to what happens after an infection or injury.
Volunteers were split into two groups: prophylactic arm and therapeutic arm.
At different times the volunteer groups were given a drug called GSK2256294, which blocks an enzyme known as soluble epoxide hydrolase (sEH), which naturally breaks down epoxy-oxylipins.
- Prophylactic arm: Participants received the drug two hours before inflammation began, to see if boosting epoxy-oxylipins early could prevent harmful immune changes. In this group there were 24 volunteers – 12 were treated, 12 untreated (placebo).
- Therapeutic arm: Participants received the drug four hours after inflammation started, mimicking real-world treatment once symptoms appear. In this group there were 24 volunteers – 12 were treated, 12 untreated (placebo).
Both approaches showed that blocking the enzyme sEH with GSK2256294 raised epoxy-oxylipin levels, accelerated pain resolution, and sharply reduced levels of intermediate monocytes in blood and tissue – the immune cells linked to chronic inflammation and disease. Interestingly, the drug did not significantly alter external symptoms, such as redness and swelling.
Further tests revealed that one epoxy-oxylipin, 12,13-EpOME, works by shutting down a protein signal called p38 MAPK, which drives monocyte transformation. This was confirmed in lab experiments and in volunteers given a p38-blocking drug.
First author Dr Olivia Bracken (UCL Department of Ageing, Rheumatology and Regenerative Medicine) said: "Our findings reveal a natural pathway that limits harmful immune cell expansion and helps calm inflammation more quickly.
"Targeting this mechanism could lead to safer treatments that restore immune balance without suppressing overall immunity.
"With chronic inflammation ranked as a major global health threat, this discovery opens a promising avenue for new therapies."
Corresponding author Professor Derek Gilroy (UCL Division of Medicine) said: "This is the first study to map epoxy-oxylipin activity in humans during inflammation.
"By boosting these protective fat molecules, we could design safer treatments for diseases driven by chronic inflammation."
He added: "This was an entirely human-based study with direct relevance to autoimmune diseases, as we used a drug already suitable for human use – one that could be repurposed to treat flares in chronic inflammatory conditions, an area currently bereft of effective therapies."
Why epoxy-oxylipins?
Scientists chose to study epoxy-oxylipins because these fat-derived molecules were known from animal research to reduce inflammation and pain, but their role in humans remained unknown. Unlike well-studied inflammatory mediators, such as histamine and cytokines, epoxy-oxylipins are part of an underexplored pathway that scientists believed could naturally calm the immune system.
Next steps
The discovery opens the door to clinical trials exploring sEH inhibitors as potential therapies for conditions like rheumatoid arthritis and cardiovascular disease.
Dr Bracken said: "For instance, rheumatoid arthritis is a condition in which the immune system attacks the cells that line your joints. sEH inhibitors could be trialled alongside existing medications to investigate if they can help prevent or slow down joint damage incurred by the condition."
Dr Caroline Aylott, Head of Research Delivery at Arthritis UK, said: "The pain of arthritis can affect how we move, think, sleep and feel, along with our ability to spend time with loved ones. Pain is incredibly complex and is affected by many different factors. We also know that everybody's pain is different.
"That is why it is important that we invest in research like this, that helps us understand what causes and influences people's experience of pain.
"We are excited to see the results of this study which has found a natural process that could stop inflammation and pain. We hope in the future that this will lead to new pain management options for people with arthritis."
The study was funded by Arthritis UK and involved researchers at UCL, King's College London, University of Oxford, Queen Mary University of London, and National Institute of Environmental Health Sciences, USA.
* Intermediate monocytes are white blood cells that help fight infection and repair tissue. In short bursts, they help coordinate the immune response and support recovery, but if they persist or grow in excess, they keep the immune system switched on, leading to chronic inflammation.
