Topical Aspirin Administration Improves Cutaneous Wound Healing in Diabetic Mice Through a Phenotypic Switch of Wound Macrophages Toward an Anti-inflammatory and Proresolutive Profile Characterized by LXA4 Release

Abstract

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.

VNS‐mediated α7nAChR signaling promotes SPM synthesis via regulation of netrin‐1 expression during LPS‐induced ALI

“…The topical application of low-dose aspirin can expedite wound healing by promoting the release of LXA4 from macrophages. 74 The removal of microglia, rather than circulating monocytes, hindered the postoperative decrease in circulating LXA4 levels, thus preventing neuroinflammation and memory impairment. 75 WRW4, a well-established and highly selective inhibitor of ALX/ FPR2, 12 counteracts the effects of LXA4.…”

“…LXA4 is hypothesized to be a critical metabolite that facilitates various anti‐inflammatory mechanisms. The topical application of low‐dose aspirin can expedite wound healing by promoting the release of LXA4 from macrophages 74 . The removal of microglia, rather than circulating monocytes, hindered the postoperative decrease in circulating LXA4 levels, thus preventing neuroinflammation and memory impairment 75 .…”

Identification and clinical validation of the role of anoikis‐related genes in diabetic foot

“…Among the numerous complications associated with diabetes, diabetic foot is highly prevalent and serious 4 . It results from neuropathy and vascular lesions caused by lower extremity tissue damage, which can lead to ulceration, infection, tissue necrosis, and even amputation 5,6 . Studies have indicated that hyperglycaemia plays a pivotal role in the development of microvascular diabetic complications.…”

S1PR1/S1PR3-YAP signaling and S1P-ALOX15 signaling contribute to an aggressive behavior in obesity-lymphoma

“…Dysregulation of lipid metabolism could render immunosuppressive microenvironment for the progression of lymphoma. In fact, the lipid metabolites, i.e., the arachidonic acid metabolites which are the major products of 12/15-lipoxygenases (ALOX15), have been turned out to be an important regulator of macrophage function [ 29 ]. ALOX15 exists in different mammalian isoenzymes designated together as 12/15-lipoxygenases since they have variable positional specificity to catalyze oxygenation at the 15-position and the 12-position of arachidonic acid.…”