Scientists at University College London (UCL) have identified a naturally occurring process that regulates inflammation, a breakthrough that could lead to new treatments for chronic diseases like arthritis, heart disease, and diabetes. The discovery, published today in Nature Communications, centers on the role of fat-derived molecules called epoxy-oxylipins in controlling the immune response.
Inflammation is a critical defense mechanism, protecting the body from infection and injury. Still, when inflammation persists unchecked, it can contribute to a range of serious health problems. Until now, the mechanisms that allow the body to transition from an active immune response to a healing phase have remained poorly understood.
The UCL research team found that epoxy-oxylipins act as natural regulators, preventing the accumulation of intermediate monocytes – a type of white blood cell associated with chronic inflammation and tissue damage. The study details how these molecules support to calm the immune system and resolve inflammation more quickly.
To investigate this process, researchers conducted a controlled experiment involving healthy volunteers. Participants received a small injection of UV-killed E. Coli bacteria into their forearm, triggering a localized inflammatory response similar to that experienced during an infection or injury. The volunteers were then divided into two groups: a “prophylactic arm” and a “therapeutic arm.”
In the prophylactic arm, 12 volunteers received a drug called GSK2256294 two hours before the induced inflammation, while 12 received a placebo. The drug works by blocking an enzyme called soluble epoxide hydrolase (sEH), which normally breaks down epoxy-oxylipins, effectively boosting their levels. The therapeutic arm followed a similar design, but participants received the drug four hours after inflammation began, mimicking a real-world treatment scenario.
Results showed that blocking sEH and increasing epoxy-oxylipin levels led to faster pain resolution in both groups. Importantly, participants who received GSK2256294 also exhibited significantly lower levels of intermediate monocytes in both their blood and the affected tissue. While the drug did not significantly alter visible symptoms like redness or swelling, the reduction in these key immune cells suggests a fundamental shift in the inflammatory process.
Further investigation revealed that a specific epoxy-oxylipin, 12,13-EpOME, suppresses a protein signaling pathway known as p38 MAPK, which is crucial for the transformation of monocytes into inflammatory cells. Laboratory experiments and additional testing in volunteers who received a separate p38 blocking drug confirmed this mechanism of action.
“Our findings reveal a natural pathway that limits harmful immune cell expansion and helps calm inflammation more quickly,” said Dr. Olivia Bracken, first author of the study from the UCL Department of Ageing, Rheumatology and Regenerative Medicine. “Targeting this mechanism could lead to safer treatments that restore immune balance without suppressing overall immunity.”
Professor Derek Gilroy, corresponding author from the UCL Division of Medicine, added, “What we have 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 also highlighted the potential for repurposing GSK2256294, noting that It’s already a drug suitable for human leverage and could be tested for treating flares in chronic inflammatory conditions.
Researchers initially investigated epoxy-oxylipins based on previous animal studies suggesting their anti-inflammatory and pain-reducing properties. However, their precise role in human biology had remained unclear. The team hypothesized that these lesser-studied molecules might offer a natural way to quiet the immune system, distinct from well-known inflammatory signals like histamine and cytokines.
The findings have prompted discussions about potential clinical trials to evaluate sEH inhibitors as treatments for rheumatoid arthritis and cardiovascular disease. Dr. Bracken explained that in rheumatoid arthritis, where the immune system attacks joint tissues, sEH inhibitors could be tested alongside existing medications to potentially prevent or slow down joint damage.
Dr. Caroline Aylott, Head of Research Delivery at Arthritis UK, emphasized the importance of this research, stating, “The pain of arthritis can affect how we move, reckon, sleep and feel, along with our ability to spend time with loved ones… 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 from UCL, King’s College London, University of Oxford, Queen Mary University of London, and the National Institute of Environmental Health Sciences, USA.
