Researchers at University College London (UCL) have identified a crucial mechanism by which the body naturally resolves inflammation. This discovery may lead to new treatments for various chronic diseases affecting millions globally.
Inflammation is a fundamental bodily defense against infection and injury. However, its uncontrolled persistence contributes to serious health conditions such as arthritis, heart disease, and diabetes. Previously, the specific processes through which the body ceases its immune response and initiates healing were not fully understood.
The study, published in Nature Communications, revealed that tiny fat-derived molecules called epoxy-oxylipins act as natural brakes on the immune system. These molecules prevent the excessive growth of intermediate monocytes, which are immune cells linked to chronic inflammation, tissue damage, and disease progression.
For the study, healthy human volunteers received a small injection of UV-killed E. coli bacteria into the forearm, which induced a brief inflammatory reaction. Volunteers were divided into two groups: a prophylactic arm and a therapeutic arm.
Both groups were given a drug named GSK2256294, which blocks soluble epoxide hydrolase (sEH), an enzyme that naturally breaks down epoxy-oxylipins. The prophylactic group received the drug two hours before inflammation started, while the therapeutic group received it four hours after inflammation commenced.
Both treatment strategies demonstrated that blocking the sEH enzyme with GSK2256294 increased epoxy-oxylipin levels. This accelerated the resolution of pain and significantly reduced levels of intermediate monocytes in both blood and tissue, the immune cells associated with chronic inflammation. The drug did not significantly alter external symptoms such as redness and swelling.
Further tests indicated that one specific epoxy-oxylipin, 12,13-EpOME, functions by deactivating a protein signal known as p38 MAPK, which drives monocyte transformation. This was confirmed through both laboratory experiments and in volunteers who received a p38-blocking drug.
Researchers stated that these findings reveal a natural pathway that limits harmful immune cell expansion and aids in resolving inflammation more quickly. Targeting this mechanism could lead to safer treatments that restore immune balance without broadly suppressing overall immunity. With chronic inflammation identified as a major global health threat, this discovery opens a promising avenue for new therapies.
Professor Derek Gilroy, a corresponding author, noted that this is the first study to map epoxy-oxylipin activity in humans during inflammation. He added that boosting these protective fat molecules could facilitate the design of safer treatments for diseases driven by chronic inflammation. The drug used is already suitable for human use, suggesting it could be repurposed to treat flares in chronic inflammatory conditions.
Epoxy-oxylipins were chosen for study based on prior animal research suggesting their role in reducing inflammation and pain, though their function in humans was unknown. Unlike well-studied inflammatory mediators, epoxy-oxylipins are part of an underexplored pathway believed to naturally calm the immune system.
The discovery paves the way for clinical trials exploring sEH inhibitors as potential therapies for conditions such as rheumatoid arthritis and cardiovascular disease. The study was funded by Arthritis UK and involved multiple research institutions.