Calcitonin gene-related peptide in diabetic wound repair: efferocytosis, inflammatory resolution, and host defense

Diabetic wounds are characterized by persistent inflammation and impaired tissue repair, with sensory neuropathy potentially disrupting the signals that coordinate these processes. Calcitonin gene-related peptide (CGRP) has emerged as a mediator connecting sensory neurons to myeloid-cell behavior. Experimental studies show that CGRP signaling through the calcitonin receptor-like receptor and receptor activity-modifying protein 1 regulates inflammatory-cell recruitment and macrophage efferocytosis, partly through thrombospondin-1. These findings extend the proposed contribution of sensory nerves beyond protection from injury to active regulation of inflammatory resolution. However, diabetes also compromises the recognition and processing of apoptotic cells, raising the possibility that ligand supplementation alone may not restore clearance. Moreover, CGRP can impair antibacterial defense in some infection models while supporting cutaneous antifungal immunity, and thrombospondin-1 has vascular effects that differ from its clearance-promoting activities. This Mini Review critically integrates these findings with recent CGRP delivery studies, distinguishing evidence from human tissue, diabetic wound models, acute injury, and infection. We argue that therapeutic development should address both neuronal signal availability and recipient-cell competence, while evaluating microbial control and perfusion alongside repair. Local CGRP delivery is a promising preclinical strategy, but its mechanisms and therapeutic window require validation in the heterogeneous environment of human diabetic foot ulcers.