Neuropeptide-Mediated Mechanisms in Diabetic Wound Healing

Diabetic wounds remain a major clinical challenge due to persistent inflammation, impaired angiogenesis and peripheral neuropathy. Emerging evidence reveals that neuropeptides—small, neuron-derived signalling molecules—play central roles in coordinating immune cells, vascular growth and tissue remodelling. In diabetes, sensory nerve fibre loss disrupts local release of key mediators such as calcitonin gene-related peptide (CGRP) and Substance P, exacerbating neutrophil persistence, macrophage dysfunction and fibroblast migration deficits. Restoration of neuropeptide signalling has been shown to rebalance pro- and anti-inflammatory cues, enhance microvascular network formation, promote keratinocyte and fibroblast motility, and accelerate extracellular matrix deposition. Understanding the molecular pathways by which neuropeptides interact with immune receptors, growth factor cascades and extracellular matrix components is informing novel biomaterial and pharmacological strategies aimed at harnessing neuro-immune cross-talk to overcome the impaired healing milieu in diabetic ulcers.

Research from Nature Portfolio

Recent studies have elucidated the role of peptidergic sensory neurons and their release of the neuropeptide CGRP in orchestrating immune responses during healing. Ablation of CGRP-expressing nociceptors impairs re-epithelialisation and muscle repair, whereas targeted delivery of a stabilised CGRP analogue restores neutrophil and macrophage dynamics, accelerates clearance of apoptotic cells and polarises macrophages towards pro-repair phenotypes in diabetic and neuropathic models. Mechanistic work reveals that CGRP signals via receptor activity-modifying protein 1 to modulate thrombospondin-1–mediated autocrine and paracrine loops in innate immune cells, representing a paradigm for neuro–immune therapeutic strategies in non-healing wounds.

Neuropeptide-Mediated Mechanisms in Diabetic Wound Healing publication trend

The graph below shows the total number of articles in neuropeptide-mediated mechanisms in diabetic wound healing across all publications each year (not limited to Nature Index journals).

Technical terms

Neuropeptide: Short chains of amino acids released by neurons that regulate immune, vascular and cellular responses during tissue repair.

Calcitonin gene-related peptide (CGRP): A sensory neuropeptide that modulates neutrophil and macrophage function to promote tissue regeneration.

Substance P (SP): A tachykinin family neuropeptide involved in vasodilation, cell migration and the recruitment of reparative cells.

Neuro-immune interaction: Bidirectional communication between the nervous and immune systems mediated by neurotransmitters and neuropeptides.

Angiogenesis: Formation of new blood vessels from existing vasculature, essential for delivering oxygen and nutrients to healing tissues.

References

1. CGRP sensory neurons promote tissue healing via neutrophils and macrophages. Nature (2024).
2. All-in-one smart dressing for simultaneous angiogenesis and neural regeneration. Journal of Nanobiotechnology (2023).
3. Loss of Innervation and Axon Plasticity Accompanies Impaired Diabetic Wound Healing. PLOS ONE (2013).
4. Neurotensin Modulates the Migratory and Inflammatory Response of Macrophages under Hyperglycemic Conditions. BioMed Research International (2013).
5. The Regenerative Potential of Substance P. International Journal of Molecular Sciences (2022).