Researchers Identify Natural Mechanism That Switches Off Inflammation

Researchers at University College London (UCL) have identified a natural mechanism in the body that appears to act as an “off switch” for inflammation, a discovery that could pave the way for treatments targeting chronic diseases such as arthritis and heart disease.

Role of Epoxy-Oxylipins in Immune Regulation

The study, published in Nature Communications, focuses on epoxy-oxylipins, a group of fat molecules produced naturally in the body. These molecules seem to regulate the immune system by preventing excessive inflammation before it escalates. The researchers found that epoxy-oxylipins can inhibit the accumulation of inflammatory immune cells associated with chronic disease and tissue damage.

Inflammation is a critical process for fighting infections and healing injuries, but when it persists over long periods, it contributes to conditions such as diabetes, cardiovascular disease, autoimmune disorders, and neurodegenerative diseases like Alzheimer’s.

Investigating the Inflammatory Response in Humans

The research team examined a biological pathway involving cytochrome P450 enzymes, which convert fatty acids into epoxy-oxylipins. While prior animal studies suggested these compounds might reduce pain and inflammation, their function in humans had not been thoroughly mapped.

To study this, healthy volunteers were injected with UV-killed E. coli bacteria in the forearm to induce a controlled inflammatory response characterized by redness, swelling, heat, and pain. Participants were then administered GSK2256294, a drug that inhibits soluble epoxide hydrolase (sEH), an enzyme that normally degrades epoxy-oxylipins. Blocking sEH increased the levels of these molecules in the body.

The experiment tested two conditions: volunteers received the drug either before inflammation onset or after symptoms had developed, simulating real-world treatment scenarios.

Selective Modulation of Immune Cells

In both groups, GSK2256294 significantly elevated levels of epoxy-oxylipins, particularly 12,13-EpOME. The treatment accelerated pain resolution and notably decreased the number of intermediate monocytes, immune cells linked to chronic inflammatory diseases. However, the drug did not substantially reduce visible signs of inflammation such as redness or swelling.

Unlike many anti-inflammatory drugs that broadly suppress the immune system and can increase infection risk, this pathway appears to selectively limit harmful immune responses without compromising overall immunity.

“Our findings reveal a natural pathway that limits harmful immune cell expansion and helps calm inflammation more quickly,” stated Dr. Olivia Bracken, first author 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.”

Insights into Monocyte Function and Inflammation

The study showed that 12,13-EpOME interferes with the p38 MAPK signaling pathway, which drives monocytes to adopt more inflammatory states. Blocking this pathway led to a marked reduction in inflammatory monocytes.

Intermediate monocytes, often elevated in diseases such as rheumatoid arthritis, lupus, obesity, HIV, Graves’ disease, and tuberculosis, may have a dual role. While they support certain T cells involved in healing and immune regulation in the short term, their prolonged presence may contribute to chronic tissue damage.

This complexity may explain the challenges in treating chronic inflammation effectively.

“This is the first study to map epoxy-oxylipin activity in humans during inflammation,” said Professor Derek Gilroy, corresponding author from the UCL Division of Medicine. “By boosting these protective fat molecules, we could design safer treatments for diseases driven by chronic inflammation.”

Potential for New Therapeutic Approaches

The findings could lead to novel therapies for rheumatoid arthritis and cardiovascular disease. Since GSK2256294 has already undergone human testing and demonstrated good tolerability, clinical trials targeting this pathway may advance more rapidly than those for entirely new drugs.

The research was funded by Arthritis UK and involved collaboration among UCL, King’s College London, University of Oxford, Queen Mary University of London, and the National Institute of Environmental Health Sciences in the United States.