Topical Aspirin administration improves cutaneous wound healing in diabetic mice through a phenotypic switch of wound macrophages toward an anti-inflammatory and pro-resolutive profile characterized by LXA4 release

Diabetic patients present a persistent inflammatory process, leading to impaired wound healing. Since non-healing diabetic wounds management shows limited results, the introduction of advanced therapies targeting and correcting the inflammatory status of macrophages in chronic wounds could be an effective therapeutic strategy to stop the sustained inflammation and to return to healing state. Here, we demonstrated in an excisional skin injury in diet-induced diabesity murine model that topic low-dose Aspirin (36µg/wound/day) administration improved cutaneous wound healing by increasing wound closure through the promotion of the inflammation resolution program of macrophages. Indeed, this treatment increased efferocytosis of wound macrophages from aspirin-treated diabetic mice compared to untreated diabetic mice. We also showed that Aspirin treatment of high fat fed mice oriented the phenotype of wound macrophages toward an anti-inflammatory and pro-resolutive profile characterized by a decrease of LTB4 production. The use of diabetic mice deficient for 5-LOX or 12/15-LOX demonstrated that these two enzymes of acid arachidonic metabolism were essential for the beneficial effect of Aspirin on wound healing. Thus, Aspirin treatment modified the balance between pro- and anti-inflammatory eicosanoids by promoting the synthesis of pro-resolving LXA4 through 5-LOX/LTA4/12/15-LOX signaling. In conclusion, the restoration of anti-inflammatory and pro-resolutive phenotype of wound macrophages by the topical administration of low-dose Aspirin represents a promising therapeutic approach in chronic wounds.