Lymphedema is characterized by the accumulation of protein-rich interstitial fluid, lipids and a significant inflammatory cell infiltrate in the limb. It causes a significant morbidity and is a common disabling disease affecting more than 250 million people worldwide, however there is no curative treatment for lymphedema.

Here, we found that dermolipectomies from patient with lymphedema exhibit inflamed gene expression profile compared to normal arm on same patient. After lipidomic analysis, we identified severe decrease in arachidonic acid-derived lipid mediators generated by the 15-lipoxygenase (15-LOX) in lymphedematous arms. Using a mouse model of lymphedema, we reproduced the ethiology of the human pathology including the loss of specialized pro-resolving lipid mediators that play essential roles in resolution of inflammation. This was associated with a lack of regulatory T cells (Treg) recruitment in the injured limb adipose tissue. Importantly, we identified the lymphatic endothelial 15-LOX was responsible for the chemoattraction and transendothelial migration of Tregs. These results were confirmed by an aggravation of lymphedema and deterioration of the lymphatic network in an original transgenic mouse model in which ALOX15 gene is selectively deleted in the lymphatic system (Prox1CreERT2;ALOX15fl/fl). Importantly, this was reversed by the injection of ALOX15 expressing lentivectors. These results provide evidence that lymphatic lipoxygenase may represent a novel therapeutic target for lymphedema by serving as a mediator of Treg invasion into lymphedematous adipose tissue.