Epoxy-oxylipins curb harmful inflammatory immune-cell expansion

Scientists have identified a natural molecular braking system that helps human inflammation resolve by limiting the expansion of potentially harmful immune cells and accelerating pain relief.

The study, led by University College London researchers and published in Nature Communications, found that fat-derived signalling molecules called epoxy-oxylipins influence how monocytes develop during an inflammatory response. Raising levels of these molecules in healthy volunteers reduced the accumulation of intermediate monocytes, a cell population associated with persistent inflammation, while shortening the time taken for pain to subside.

Researchers tested the pathway using GSK2256294, a selective inhibitor of soluble epoxide hydrolase, or sEH. The enzyme normally breaks down epoxy-oxylipins. Blocking it increased concentrations of two protective molecules, 12,13-EpOME and 14,15-EET, allowing the team to examine whether preserving these compounds altered the course of inflammation in people.

Healthy male volunteers received a small intradermal injection of ultraviolet-killed Escherichia coli in the forearm, a well-established experimental model that produces a temporary, self-resolving inflammatory reaction marked by pain, redness, warmth and swelling. Participants were enrolled in separate prophylactic and therapeutic groups so investigators could test the drug before inflammation began and after it had already developed.

In each arm, 24 volunteers took part, with 12 receiving GSK2256294 and 12 receiving placebo. Those in the prophylactic group were given treatment two hours before the inflammatory challenge, while those in the therapeutic group received it four hours afterwards, closer to the way an anti-inflammatory medicine might be used after symptoms appear.

Both approaches increased epoxy-oxylipin activity and significantly reduced circulating intermediate monocytes that otherwise expanded during the inflammatory response. Tissue samples also showed fewer intermediate monocytes at the inflamed site and fewer CD4 T cells, suggesting that the pathway influences both circulating and local immune-cell behaviour.

The treatment also hastened the resolution of pain. However, investigators found no significant effect on visible inflammatory signs such as redness, swelling or increased skin temperature. That distinction indicates the pathway may alter specific cellular and sensory aspects of inflammation without broadly suppressing the entire defensive response.

Laboratory experiments identified 12,13-EpOME as a key mediator. The molecule blocked the transition of classical monocytes into intermediate monocytes by inhibiting p38 mitogen-activated protein kinase, or p38 MAPK, a signalling pathway involved in inflammatory cell differentiation. Researchers reproduced the effect in laboratory tests using p38 inhibition and in healthy volunteers treated with losmapimod, a p38 MAPK inhibitor.

Researchers tracked enzymes that make and degrade epoxy-oxylipins at the inflammatory site. Cytochrome P450 enzymes and epoxide hydrolase forms changed across the response, while production of lipid mediators rose as inflammation evolved. The pattern supported the idea that resolution is an organised programme, with regulatory signals, rather than a return to baseline.

The findings give researchers a more detailed picture of how inflammation actively resolves rather than simply fading when the initial trigger disappears. Intermediate monocytes have been linked to chronic inflammatory states and tissue damage, making the control of their expansion a possible therapeutic target.

First author Dr Olivia Bracken said the results reveal a natural pathway that limits harmful immune-cell expansion and helps calm inflammation more quickly. She said targeting the mechanism could offer a way to restore immune balance without suppressing overall immunity, an important consideration because broad immunosuppression can increase vulnerability to infection.

Professor Derek Gilroy, the study’s corresponding author, said the work was the first to map epoxy-oxylipin activity in humans during inflammation. He said preserving these protective lipid molecules could provide a basis for designing treatments for disorders in which inflammation fails to resolve normally.

The researchers stressed that the work was conducted in healthy volunteers using a controlled model of short-lived inflammation, rather than in patients with established chronic inflammatory disease. Further studies would therefore be needed to determine whether sEH inhibition can produce meaningful clinical benefits in conditions such as arthritis, cardiovascular disease or diabetes.