Researchers Discover the Body’s Hidden “Off Switch” for Inflammation

Scientists have uncovered a previously underexplored mechanism that may act as one of the body’s natural “off switches” for inflammation.

Your body is constantly fighting microscopic battles. The surprising part is not how inflammation starts, but how it knows when to stop.

Now, scientists at University College London (UCL) say they have uncovered one of the body’s hidden “off switches” for inflammation, a discovery that could eventually lead to new treatments for diseases ranging from arthritis to heart disease.

The study, published in Nature Communications, identifies a group of naturally produced fat molecules called epoxy-oxylipins that appear to calm the immune system before inflammation spirals out of control. Researchers found these molecules can block the buildup of inflammatory immune cells linked to chronic disease and tissue damage.

Why Inflammation Becomes Dangerous

Inflammation is both essential and potentially dangerous. In the short term, it helps the body destroy infections and repair injuries. But when inflammation lingers for months or years, it becomes a driving force behind some of the world’s most common illnesses, including diabetes, cardiovascular disease, autoimmune disorders, and even neurodegenerative conditions like Alzheimer’s.

This study focused on an overlooked biological pathway involving enzymes known as cytochrome P450s, which transform fatty acids into signaling molecules called epoxy-oxylipins. Earlier animal research hinted these compounds might reduce pain and inflammation, but their role in humans had never been mapped in detail.

To investigate, researchers triggered a controlled inflammatory response in healthy volunteers using injections of UV-killed E. coli bacteria into the forearm. The temporary reaction caused redness, swelling, heat, and pain similar to what happens after infection or injury.

Participants then received a drug called GSK2256294, which blocks an enzyme known as soluble epoxide hydrolase (sEH). Normally, sEH rapidly breaks down epoxy-oxylipins. By blocking the enzyme, researchers were able to increase levels of the molecules naturally produced by the body.

The experiment tested two scenarios. Some volunteers received the drug before inflammation started, while others received it after symptoms had already appeared, mimicking real-world treatment.

A More Targeted Anti-Inflammatory Response

In both groups, the drug significantly increased levels of key epoxy-oxylipins, especially a molecule called 12,13-EpOME. The treatment also sped up pain resolution and sharply reduced levels of “intermediate monocytes,” immune cells increasingly linked to chronic inflammatory disease.

Interestingly, the drug did not dramatically reduce outward signs of inflammation like redness or swelling.

Many anti-inflammatory drugs suppress broad parts of the immune system, which can leave patients vulnerable to infections or other side effects. In contrast, the newly identified pathway appears to selectively limit harmful immune escalation without shutting down normal immune defenses.

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

The Complex Role of Immune Cells

The researchers discovered that 12,13-EpOME works by interfering with a cellular signaling pathway called p38 MAPK, which helps drive the transformation of monocytes into more inflammatory states. When researchers blocked this pathway, inflammatory monocyte levels fell dramatically.

The work also revealed an unexpected twist about these immune cells themselves.

Intermediate monocytes are often considered harmful because they are elevated in diseases such as rheumatoid arthritis, lupus, obesity, HIV, Graves’ disease, and tuberculosis. But the new findings suggest the cells may play a more complicated role. In the short term, they appear to help support certain T cells involved in healing and immune regulation. When they persist too long, however, they may contribute to chronic tissue damage.

That dual nature could help explain why chronic inflammation is so difficult to treat.

“This is the first study to map epoxy-oxylipin activity in humans during inflammation,” said corresponding author Professor Derek Gilroy of the UCL Division of Medicine.

“By boosting these protective fat molecules, we could design safer treatments for diseases driven by chronic inflammation.”

The researchers say the findings could eventually open the door to new therapies for rheumatoid arthritis and cardiovascular disease. Because GSK2256294 has already been tested in humans and shown to be well tolerated, future clinical trials may move faster than they would for an entirely new drug.

Reference: “Epoxy-oxylipins direct monocyte fate in inflammatory resolution in humans” by Olivia V. Bracken, Parinaaz Jalali, James R. W. Glanville, Larrissa Benvenutti, Emma S. Chambers, Hugh Trahair, Madhur Motwani, Karen T. Feehan, Jamie G. Evans, Jhonatan de Souza Carvalho, Roel P. H. De Maeyer, Arne N. Akbar, Fred B. Lih, Darryl C. Zeldin, David Bishop-Bailey, Matthew L. Edin and Derek W. Gilroy, 16 January 2026, Nature Communications.
DOI: 10.1038/s41467-025-67961-5

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.

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