Scientists at University College London have uncovered a natural “off switch” for inflammation in humans. The discovery could pave the way for new treatments for arthritis, heart disease and other chronic conditions driven by runaway immune responses.
Scientists have identified a natural “brake” in the human immune system that helps switch off inflammation before it causes lasting damage — a discovery that could reshape how doctors treat chronic diseases such as arthritis and heart disease.
In a human study led by researchers at University College London, tiny fat-derived molecules called epoxy-oxylipins were shown to act as internal stop signals for the immune system. When boosted with a drug, these molecules helped resolve pain faster and prevented the build-up of a type of white blood cell linked to long-term inflammation.
The work, published in Nature Communications, offers fresh hope for millions of people living with chronic inflammatory conditions, which are a major driver of disability and early death worldwide.
Inflammation is the body’s first line of defense against infection or injury. It causes redness, heat, swelling and pain as immune cells rush to the site of damage. In a healthy response, this reaction is short-lived: once the threat is cleared, the body shifts into healing mode and inflammation fades.
But when that “off switch” fails, the immune system can stay stuck in fight mode. Over time, this smoldering inflammation can damage tissues and organs, contributing to conditions such as rheumatoid arthritis, cardiovascular disease and type 2 diabetes.
The UCL team set out to understand how the body decides to stand down its immune response. They focused on epoxy-oxylipins, fat-based molecules that animal studies had suggested could reduce inflammation and pain, but whose role in humans was largely unknown.
To study this in real time, the researchers created a controlled, short-lived inflammatory reaction in healthy volunteers. Participants received a tiny injection of ultraviolet-killed E. coli bacteria into the skin of the forearm, triggering the familiar signs of acute inflammation: pain, redness, warmth and swelling.
Forty-eight volunteers were divided into two groups. In one “prophylactic” arm, participants were given a drug called GSK2256294 two hours before the injection. In the other “therapeutic” arm, they received the drug four hours after inflammation had begun, mimicking how a treatment might be used once symptoms appear.
GSK2256294 blocks an enzyme called soluble epoxide hydrolase, or sEH, which normally breaks down epoxy-oxylipins. By inhibiting sEH, the drug raises levels of these protective fat molecules in the body.
Across both groups, the researchers found that blocking sEH boosted epoxy-oxylipin levels, sped up the resolution of pain and sharply reduced levels of so-called intermediate monocytes in the blood and tissue. These white blood cells are helpful in short bursts, helping fight infection and repair tissue, but when they linger or expand, they can keep the immune system switched on and drive chronic inflammation.
“Our findings reveal a natural pathway that limits harmful immune cell expansion and helps calm inflammation more quickly,” first author Olivia Bracken, a research fellow in the UCL Department of Ageing, Rheumatology and Regenerative Medicine, said in a news release.
Importantly, the drug’s effects were seen inside the body rather than on the skin’s surface. While pain resolved more quickly, visible signs such as redness and swelling did not change significantly, suggesting the treatment was altering deeper immune processes without simply masking symptoms.
Further tests homed in on one particular epoxy-oxylipin, called 12,13-EpOME. The team found that this molecule works by shutting down a protein signal known as p38 MAPK, which drives the transformation of monocytes into more inflammatory forms. This mechanism was confirmed both in laboratory experiments and in volunteers who were given a separate drug that blocks p38.
By mapping how these molecules behave in humans during inflammation, the study opens a new window into the body’s own tools for restoring balance.
“This is the first study to map epoxy-oxylipin activity in humans during inflammation,” added corresponding author Derek Gilroy, a professor of experimental inflammation and pharmacology in the UCL Division of Medicine.
Unlike many immune-suppressing drugs that can leave patients more vulnerable to infections, targeting epoxy-oxylipins and the sEH enzyme could offer a way to nudge the immune system back toward normal without shutting it down completely. That makes the approach especially attractive for long-term conditions that flare repeatedly over many years.
The discovery is particularly relevant for autoimmune and inflammatory diseases such as rheumatoid arthritis, where the immune system mistakenly attacks the body’s own tissues. The researchers note that sEH inhibitors like GSK2256294 could potentially be tested alongside existing arthritis medications to see if they help prevent or slow joint damage.
For people living with arthritis, better pain control and inflammation management could be life-changing.
“That is why it is important that we invest in research like this, that helps us understand what causes and influences people’s experience of pain,” Caroline Aylott, head of research delivery at Arthritis UK, which funded the study, said in the news release.
The study involved collaborators at UCL, King’s College London, the University of Oxford, Queen Mary University of London and the U.S. National Institute of Environmental Health Sciences.
While the findings are early and come from a carefully controlled experimental model in healthy volunteers, they set the stage for clinical trials in people with chronic inflammatory diseases. Future studies are expected to test sEH inhibitors in conditions such as rheumatoid arthritis and cardiovascular disease, to see whether enhancing the body’s own epoxy-oxylipin “brake” can reduce flares, protect tissues and improve quality of life.
As chronic inflammation continues to be recognized as a major global health threat, the work points toward a new class of treatments that work with, rather than against, the body’s natural healing systems.
“With chronic inflammation ranked as a major global health threat, this discovery opens a promising avenue for new therapies,” added Bracken.
Source: University College London