Scientists Finally Found the Natural Off Switch for Human Inflammation

Inflammation is the body’s battle cry. When bacteria invade or tissue is injured, immune cells rush in, blood vessels widen, and the familiar signs appear: pain, heat, redness, swelling. It is a fierce and necessary response, designed to protect. But every battle needs an ending. When inflammation refuses to switch off, it can quietly turn destructive, driving long-term illness and damage across the body.

For years, scientists have understood how inflammation starts, yet the question of how the body tells itself to stop has remained surprisingly mysterious. Now, researchers at University College London believe they have uncovered a crucial part of that missing story. Their findings reveal a natural molecular brake that helps calm the immune system, guiding it away from prolonged attack and toward healing.

Published in Nature Communications, the study shines a light on tiny fat-derived molecules called epoxy-oxylipins, and the unexpected power they hold in shaping the immune response in humans.

A Quiet Signal Hidden in Fat

Epoxy-oxylipins are not the usual stars of inflammation research. Unlike well-known mediators such as histamine or cytokines, these molecules belong to a largely underexplored pathway. Scientists knew from animal studies that they could reduce inflammation and pain, but their role in the human body during real inflammatory events remained unknown.

The UCL team suspected these molecules might act not as triggers, but as peacemakers. Instead of amplifying the immune response, epoxy-oxylipins appeared to gently restrain it, preventing the immune system from doing more harm than good. The challenge was proving this in people, not animals, and in a way that captured inflammation as it unfolds.

Recreating Inflammation, Safely and Precisely

To observe this process in action, researchers turned to healthy human volunteers. Each participant received a tiny injection of UV-killed E. coli bacteria into the forearm. The bacteria could not cause infection, but they reliably triggered a short-lived inflammatory reaction. Pain, redness, warmth, and swelling followed, closely mimicking what happens during everyday infections or minor injuries.

This controlled setting allowed scientists to watch inflammation rise and fall in real time. The volunteers were divided into two groups, each designed to answer a different question about timing and treatment.

One group received an experimental drug before inflammation began. The other received the same drug after symptoms were already underway, reflecting how treatment usually happens in real life.

Protecting Early or Healing Later

The drug used in the study, GSK2256294, targets a specific enzyme known as soluble epoxide hydrolase, or sEH. This enzyme normally breaks down epoxy-oxylipins. By blocking it, the drug allows levels of these protective fat molecules to rise naturally in the body.

In the prophylactic group, volunteers took the drug two hours before inflammation was triggered. In the therapeutic group, participants received it four hours after inflammation had already started. Each group included treated individuals and others who received a placebo, ensuring the results could be compared clearly.

What followed surprised even the researchers.

The Immune Cells That Refuse to Let Go

As inflammation unfolded, scientists closely tracked a particular group of immune cells known as intermediate monocytes. These cells play a role in fighting infection, but when they grow unchecked, they are strongly linked to chronic inflammation, tissue damage, and disease progression.

In both volunteer groups, blocking the sEH enzyme led to a sharp reduction in these problematic immune cells, not just in the blood, but also in inflamed tissue. At the same time, participants experienced faster resolution of pain.

Interestingly, outward signs such as redness and swelling did not change significantly. The real shift was happening beneath the surface, within the immune system itself. The body was learning how to stand down more efficiently, even if the skin still looked inflamed.

Following the Molecular Trail

To understand how epoxy-oxylipins exert this calming effect, the researchers dug deeper. They identified one molecule in particular, 12,13-EpOME, as a key player.

This epoxy-oxylipin was found to shut down a protein signaling pathway called p38 MAPK. This signal normally drives monocytes to transform into the intermediate form associated with long-term inflammation. By silencing this pathway, 12,13-EpOME effectively stopped the immune system from creating more of the cells that keep inflammation alive.

The team confirmed this mechanism not only in laboratory experiments, but also in human volunteers given a drug that blocks p38 MAPK directly. The results aligned perfectly, strengthening the evidence that epoxy-oxylipins act through this specific molecular switch.

A Natural Brake, Not an Immune Shutdown

For Dr. Olivia Bracken, the study’s first author from UCL’s Department of Aging, Rheumatology and Regenerative Medicine, the implications are profound.

“Our findings reveal a natural pathway that limits harmful immune cell expansion and helps calm inflammation more quickly,” she said.

Crucially, this pathway does not silence the immune system altogether. Instead, it restores balance. The immune response still occurs, but it does not spiral into prolonged aggression.

Dr. Bracken emphasized that targeting this mechanism could lead to safer treatments that reduce harmful inflammation without leaving patients vulnerable to infection.

“With chronic inflammation ranked as a major global health threat,” she noted, “this discovery opens a promising avenue for new therapies.”

Mapping an Entirely Human Pathway

Professor Derek Gilroy, corresponding author and member of UCL’s Division of Medicine, highlighted another milestone. This study, he explained, is the first to map epoxy-oxylipin activity in humans during inflammation.

By working exclusively with human volunteers and a drug already suitable for human use, the research avoids many of the pitfalls that prevent laboratory discoveries from translating into real treatments.

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

He added that the approach could be especially valuable for autoimmune diseases, where current treatment options are limited and often blunt in their effects.

Opening the Door to New Trials

The findings have already pointed researchers toward the next phase. Clinical trials are now being considered to explore sEH inhibitors as potential therapies for conditions such as rheumatoid arthritis and cardiovascular disease.

Dr. Bracken explained how this might work in practice. Rheumatoid arthritis occurs when the immune system attacks the cells lining the joints, leading to pain and damage over time. sEH inhibitors could be tested alongside existing medications to see whether they help prevent or slow this damage by stopping harmful immune cell expansion early.

The Human Cost of Chronic Pain

The potential impact extends beyond immune biology. Dr. Caroline Aylott, Head of Research Delivery at Arthritis UK, underscored the human dimension of the discovery.

“The pain of arthritis can affect how we move, think, sleep and feel,” she said, as well as how people connect with those they love. Pain, she explained, is deeply complex and varies widely from person to person.

That complexity is exactly why understanding the biological roots of pain matters so much. Research that uncovers natural processes capable of calming inflammation offers hope for more personalized and effective pain management in the future.

Dr. Aylott welcomed the study’s findings, describing them as an exciting step toward new options for people living with arthritis.

Why This Discovery Matters

Chronic inflammation sits at the heart of many of the world’s most serious diseases, quietly damaging tissues and wearing down the body over time. Current treatments often rely on suppressing the immune system broadly, a strategy that can bring serious side effects and risks.

This research reveals something different: a natural off-switch built into the human immune system itself. By understanding how epoxy-oxylipins limit harmful immune cell growth and accelerate pain resolution, scientists have uncovered a way to work with the body rather than against it.

The discovery shows that inflammation is not just about attack and defense, but about timing, restraint, and recovery. If future therapies can safely boost this built-in braking system, millions of people living with chronic inflammatory diseases could benefit from treatments that heal without silencing the immune system entirely.

In that quiet molecular signal from fat-derived molecules, the body may already hold the blueprint for restoring balance.