What is it about?

Bioactive lipids called oxylipins are usually studied individually to determine how they regulate inflammation, however in response to wounding, they are made in complex mixtures, not one at a time. This raises questions about how they (especially the more abundant lipids) might be acting holistically and if so, what are the mechanisms involved. Here, we mapped out the anti-inflammatory/pro-resolving actions of an enzyme that makes several oxylipins, called 12/15-lipoxygenase. Mice lacking this enzyme showed many defects in wound healing, that mapped to a deficiency of oxylipin ligands for a well known transcription factor and transrepressor called peroxisome proliferator-activated receptor gamma (PPARg). The lack of ligands led to overactivity of inflammasome and cytokine signaling (interleukin-6, transforming growth factor-b) that prevented normal healing. The lipids involved were abundant monohydroxy species, formed by oxygenation of unsaturated fatty acids released in direct response to wounding. Lipids from 12/15-lipoxygenase have long been known to be ligands for PPARg, but their holistic role in driving wound healing/inflammation resolution together via this process, and the specific transcriptional regulation of this by the lipids is a new discovery.

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Why is it important?

Defective wound healing is a common and significant clinical problem, that is especially relevant to patients with chronic metabolic diseases and in aging. Local application of agents that promote pro-healing pathways may help to treat poorly healing wounds, reducing infection risk and improving morbidity.

Perspectives

The process of inflammation leads to many lipid signaling pathways being switched on together, with complex mixtures of bioactive species generated. However, research into the roles of bioactive lipids in inflammation has tended to focus on working out their functions individually (and often using pharmacological amounts). Here, we decided to look more holistically at lipid signaling after skin wounding, considering overall what lipids are made, in what amounts, and whether they then act in concert (rather than singly) to regulate the complex process of healing. Our data show that looking holistically at lipid signaling provides a new perspective when researching complex tissue responses to injury, and taking this approach could enable us to develop more effective treatments for poorly healing wounds.

Valerie O'Donnell
Cardiff University

Read the Original

This page is a summary of: 12/15-lipoxygenase orchestrates murine wound healing via PPARγ-activating oxylipins acting holistically to dampen inflammation, Proceedings of the National Academy of Sciences, September 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2502640122.
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