Chemokine-driven angiogenesis and inflammation in diabetic wounds: Mechanistic insights and therapeutic strategies

Chronic diabetic wounds are characterized by impairment of the normal wound healing process resulting from persistent inflammation, impaired angiogenesis, and elevated infection risk. Chemokines are small chemotactic cytokines that can regulate immune cell recruitment, vascularization, and matrix remodeling. This review examines the roles of six key chemokines, including CXCL8, CXCL12, CCL2, CCL5, CXCL5, and CCL28, and their receptors in diabetic wound pathophysiology. Hyperglycemia-induced overexpression of CXCL8 and CXCL5 has been found to prolong inflammation and impair endothelial progenitor cell (EPC) function via CXCR1/2-mediated extracellular signal-regulated kinase (ERK)/RelA (p65) signaling. Conversely, the CXCL12/CXCR4 axis promotes EPC homing and neovascularization, while CCL2 is essential for timely macrophage infiltration and collagen deposition. CCL5 contributes to both inflammatory persistence and angiogenesis through CCR5 and co-receptors. CCL28–CCR10 signaling suppresses endothelial nitric oxide synthase (eNOS), exacerbating microvascular dysfunction. By integrating chemokine crosstalk into a network model that links inflammatory chronicity to vascular failure, this review extends prior ligand-centered overviews and identifies systems-level therapeutic entry points in diabetic foot ulcers. We highlight innovative interventions, including neutralizing antibodies, receptor-blocking peptides and biomaterial-based delivery, to restore chemokine balance and enhance healing. Overall, this mechanistic framework underscores chemokines as viable candidates for precision-targeted regenerative therapies for the management of chronic diabetic foot ulcers.