Omentin-1 promotes diabetic wound healing by regulating macrophage efferocytosis and M2 polarization

Diabetes is a metabolic disorder that significantly impacts human health, with 25% of patients suffering from diabetic ulcers. Chronic persistent inflammation is one of the primary factors impeding wound healing in diabetes. As a recently identified adipocytokine, omentin-1 (also known as intelectin-1, ITLN1) demonstrates significant expression levels in the omentum, subcutaneous adipose tissue, and vascular endothelium, exhibiting potent anti-inflammatory characteristics. Emerging evidence indicates that this adipokine plays a crucial protective role in multiple inflammatory disorders, particularly in the pathogenesis of atherosclerosis, osteoarthritis, and inflammatory bowel disease. However, its therapeutic potential in diabetic wound healing remains unclear. Our experimental data demonstrated a marked downregulation of omentin-1 expression in cutaneous tissues obtained from the Streptozotocin (STZ)-induced diabetic murine model. Local administration of recombinant omentin-1 improved efferocytosis in impaired macrophages within the wound bed and promoted macrophage phenotypic switching to the reparative M2 phenotype, thereby attenuating inflammatory responses and accelerating wound healing in diabetic mice. Further mechanistic studies revealed that omentin-1 enhanced the expression of the key efferocytosis receptor MERTK (mer proto-oncogene tyrosine kinase) in diabetic wounds and facilitated macrophage efferocytosis through modulation of the downstream SRC/PI3K/Akt signaling cascade. Additionally, omentin-1 facilitated the polarization of macrophages toward the M2 phenotype and attenuated the inflammatory responses induced by lipopolysaccharide (LPS). The findings of this study indicate that omentin-1 suggests its potential as a candidate for developing novel adjunctive therapies for chronic non-healing diabetic wounds. • Omentin-1 expression is reduced in the skin tissues of diabetic mice and in high glucose-cultured THP-1 cells. • Omentin-1 promotes diabetic wound healing via enhanced macrophage efferocytosis and M2 polarization, exerting anti-inflammatory effects. • Omentin-1 facilitates macrophage efferocytosis by regulating the MERTK-mediated SRC/PI3K/Akt signaling pathway. • SRC is also involved in omentin-1's regulation of M2 macrophage polarization. • The adipokine omentin-1 may serve as a therapeutic agent for diabetic wounds.