| Autor: |
Audrey Zamora, benoit Chaput, Nicolas Fazilleau, Julie malloizel-delaunay, Alessandra Bura-Rivière, Anne-Catherine Prats, Barbara Garmy-Susini, Emeline Benuzzi, Francoise Pujol, Florian Morfoisse, Vincent Baillif, Eric Lacazette, Jean Galitzky, Anne Bouloumié, Marc Dubourdeau |
| Rok vydání: |
2022 |
| Zdroj: |
ORCID |
| DOI: |
10.21203/rs.3.rs-2167689/v1 |
| Popis: |
Lymphedema (LD) 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 150 million people worldwide, however there is no yet curative treatment. Here, we found that LD tissues from patients exhibit inflamed gene expression profile compared to their normal arm. Lipidomic analysis revealed severe decrease in arachidonic acid-derived lipid mediators generated by the 15-lipoxygenase (15-LO) in lymphedematous arms. Using a mouse model of lymphedema, we reproduced the etiology of the human pathology including the loss of specialized pro-resolving lipid mediators that play essential role in resolution of inflammation. This was associated with a lack of nonlymphoid PPARg-positive regulatory T cells (Treg) recruitment in the injured limb adipose tissue. Importantly, we identified the lymphatic endothelial 15-LO as responsible for the chemoattraction and survival of this Treg subpopulation. These results were confirmed by an aggravation of LD and degradation of the lymphatic network in an original transgenic mouse model in which ALOX15 gene has been selectively deleted in the lymphatic system (ALOX15lecKO). Importantly, this phenotype was rescued by the injection of ALOX15-expressing lentivectors. These results provide evidence that lymphatic 15-LO may represent a novel therapeutic target for LD by serving as a mediator of nonlymphoid Treg cell population invasion into lymphedematous adipose tissue to resolve inflammation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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