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, the inventors found that dermolipectomies from patient with
lymphedema exhibit inflamed
gene expression profile compared to normal arm on same patient. After lipidomic analysis, the inventors 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, they reproduced the
etiology 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, the inventors 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. Importantly, this was reversed by the injection of 15-LOX 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.