Body’s ‘Off Switch’ for Inflammation Discovered, Offering Hope for Chronic Disease Treatment

Researchers at University College London (UCL) have identified a natural mechanism that regulates inflammation, potentially paving the way for safer and more effective treatments for chronic diseases like arthritis, heart disease, and diabetes. The breakthrough, published in Nature Communications, centers around the role of fat-derived molecules called epoxy-oxylipins in controlling the immune response.

The Problem with Uncontrolled Inflammation

Inflammation is a crucial defense mechanism, protecting the body from infection and injury. However, when inflammation persists or becomes chronic, it can contribute to a wide range of serious health conditions. Until recently, the precise mechanisms governing the body’s ability to switch off inflammation remained unclear.

Epoxy-Oxylipins: Natural Regulators of the Immune System

The study revealed that epoxy-oxylipins act as natural brakes on the immune system, preventing the overgrowth of intermediate monocytes – a type of white blood cell associated with chronic inflammation and tissue damage. These molecules appear to facilitate the body transition from an active immune attack to a healing phase.

How the Research Was Conducted

Researchers conducted a controlled experiment involving healthy volunteers. Participants received a small injection of UV-killed E. Coli bacteria into their forearm, triggering a temporary inflammatory response. The volunteers were then divided into two groups: a prophylactic arm and a therapeutic arm.

• Prophylactic Arm: Participants received a drug called GSK2256294 – which blocks the enzyme soluble epoxide hydrolase (sEH), preventing the breakdown of epoxy-oxylipins – two hours before inflammation began. This tested whether boosting epoxy-oxylipins could prevent harmful immune changes.
• Therapeutic Arm: Participants received GSK2256294 four hours after inflammation started, mimicking a real-world treatment scenario.

Each arm included 12 treated volunteers and 12 receiving a placebo.

Key Findings: Boosting Epoxy-Oxylipins Reduces Inflammation

In both groups, blocking sEH increased levels of epoxy-oxylipins. Participants who received the drug experienced faster pain resolution and significantly lower levels of intermediate monocytes in both their blood and affected tissue. Notably, the medication did not significantly alter visible symptoms like redness or swelling.

Further investigation pinpointed a specific epoxy-oxylipin, 12,13-EpOME, which suppresses a protein signaling pathway called p38 MAPK. This pathway drives the transformation of monocytes, contributing to inflammation. Laboratory experiments and additional testing confirmed this mechanism.

Expert Perspectives

“Our findings reveal a natural pathway that limits harmful immune cell expansion and helps calm inflammation more quickly,” said Dr. Olivia Bracken, lead 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, “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 also highlighted the potential to repurpose existing drugs for treating inflammatory flares.

Future Directions: Clinical Trials for Arthritis and Heart Disease

The research opens the door for clinical trials to evaluate sEH inhibitors as potential treatments for conditions like rheumatoid arthritis and cardiovascular disease. Researchers suggest that sEH inhibitors could be used alongside existing arthritis medications to prevent or slow down joint damage.

Dr. Caroline Aylott, Head of Research Delivery at Arthritis UK, emphasized the importance of understanding the complexities of pain and the potential of this research to lead to new pain management options for people with arthritis. Arthritis UK funded the study.

Study Collaboration

The study was a collaborative effort involving researchers from UCL, King’s College London, University of Oxford, Queen Mary University of London, and the National Institute of Environmental Health Sciences, USA.