Researchers at University College London (UCL) have made a groundbreaking discovery that could transform the treatment of chronic diseases. They have identified a crucial mechanism that helps the body naturally switch off inflammation, a finding that could lead to new therapies for conditions affecting millions worldwide.
Inflammation serves as the body’s primary defense against infection and injury. However, when this response fails to deactivate properly, it can lead to severe health issues such as arthritis, heart disease, and diabetes. Until now, the scientific community struggled to understand how the body decides to cease the immune ‘fight’ response and commence the healing process.
Published in the journal Nature Communications, the study reveals that tiny fat-derived molecules known as epoxy-oxylipins act as natural brakes on the immune system. These molecules inhibit the proliferation of certain immune cells, specifically intermediate monocytes, which are linked to chronic inflammation and subsequent tissue damage.
Understanding the Mechanism
The research involved healthy human volunteers who received a small injection of UV-killed E. coli bacteria into their forearms, triggering a short-lived inflammatory reaction. This reaction, characterized by pain, redness, heat, and swelling, mimics the body’s response to infection or injury.
Participants were divided into two groups: the prophylactic arm and the therapeutic arm. Each group received a drug called GSK2256294, which blocks an enzyme known as soluble epoxide hydrolase (sEH). This enzyme typically breaks down epoxy-oxylipins.
Prophylactic and Therapeutic Approaches
- Prophylactic Arm: Participants received the drug two hours before inflammation began. This approach aimed to determine if early enhancement of epoxy-oxylipins could prevent harmful immune changes. The group comprised 24 volunteers, split equally between treated and placebo groups.
- Therapeutic Arm: Participants were given the drug four hours after inflammation onset, simulating real-world treatment following symptom emergence. This group also consisted of 24 volunteers, with a similar division between treated and placebo groups.
Both strategies demonstrated that inhibiting the sEH enzyme with GSK2256294 increased epoxy-oxylipin levels, accelerated pain resolution, and significantly reduced intermediate monocyte levels in blood and tissue. Notably, the drug did not substantially alter external symptoms such as redness and swelling.
Scientific Insights and Expert Opinions
Further tests identified that one epoxy-oxylipin, 12,13-EpOME, functions by deactivating a protein signal called p38 MAPK, which drives monocyte transformation. This was corroborated through lab experiments and trials involving a p38-blocking drug.
“Our findings reveal a natural pathway that limits harmful immune cell expansion and helps calm inflammation more quickly,” said Dr. Olivia Bracken, first author and researcher at UCL’s 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 UCL’s Division of Medicine, emphasized the significance of the study, stating, “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.”
Why Epoxy-Oxylipins?
Epoxy-oxylipins were chosen for this study because, although known from animal research to reduce inflammation and pain, their role in humans was previously unexplored. Unlike well-known inflammatory mediators like histamine and cytokines, epoxy-oxylipins belong to an underexplored pathway believed to naturally calm the immune system.
Future Implications
The discovery paves the way for clinical trials exploring sEH inhibitors as potential therapies for conditions such as rheumatoid arthritis and cardiovascular disease. Dr. Bracken noted, “For instance, rheumatoid arthritis is a condition in which the immune system attacks the cells that line your joints. sEH inhibitors could be trialed 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, expressed optimism about the findings, stating, “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.”
“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,” added Dr. Aylott.
The study was funded by Arthritis UK and involved collaboration with researchers from King’s College London, University of Oxford, Queen Mary University of London, and the National Institute of Environmental Health Sciences in the USA.
This breakthrough discovery not only enhances our understanding of inflammation but also opens new avenues for developing treatments that could significantly improve the lives of those suffering from chronic inflammatory diseases.
