Cutaneous Innervation in Impaired Diabetic Wound Healing

From Nowak and coworkers at Northwestern.

Type 2 diabetes (T2D) is associated with several potential comorbidities, among them impaired wound healing, chronic ulcerations, and the requirement for lower extremity amputation. Disease-associated abnormal cellular responses, infection, immunological and microvascular dysfunction, and peripheral neuropathy are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory nerve afferents and nerve-derived modulators, which communicate with epidermal keratinocytes and dermal fibroblasts bidirectionally to effect normal wound healing after trauma. However, the mechanisms through which cutaneous innervation modulates wound healing are poorly understood, especially in humans. Better understanding of these mechanisms may provide the basis for targeted treatments for chronic diabetic wounds. This review provides an overview of wound healing pathophysiology with a focus on neural involvement in normal and diabetic wound healing, as well as future therapeutic perspectives to address the unmet needs of diabetic patients with chronic wounds.

Cellular mechanisms involved in normal wound healing and their impairment in chronic diabetic wounds. Top : In contrast to healing in normal skin (left), healing in diabetic skin (right) is impaired. Chronic diabetic wounds have an epidermis that migrates poorly, an influx of dysfunctional inflammatory cells, and surface biofilm. In addition to impaired proliferation and migration of fibroblasts and endothelial cells in diabetic wounds, sensory innervation is deficient, with a reduction in intraepidermal nerve fiber density. Bottom : Normal wound repair involves a temporal sequence of overlapping phases: hemostasis, inflammation, cell proliferation and migration, and remodeling. Unlike normal wounds, chronic wounds are stalled in the inflammatory phase. Neuropeptides have crucial roles at each stage of wound repair and are dysregulated in diabetes. While tachykinins substance P (SP) and neuropeptide Y (NPY), as well as calcitonin gene-related peptide (CGRP) are downregulated during diabetic wound healing, corticotropin releasing factor (CRF), α-melanocorticotropin releasing hormone (α-MSH), and neurotensin (NT) are upregulated, contributing to delayed healing.

proliferation and migration of fibroblasts and endothelial cells in diabetic wounds, sensoryinnervationisdeficient,withareductioninintra-epidermalnervefiberdensity.Bottom.Normalwoundrepairinvolvesatemporalsequenceofoverlappingphases:hemostasis,inflammation,cellproliferationandmigration,andremodeling.Unlike normalwounds,chronicwoundsarestalledintheinflammatoryphase.Neuropeptideshavecrucialrolesateachstageofwoundrepairandaredysregulatedindiabetes.WhiletachykininssubstanceP(SP)andneuropeptideY(NPY),aswellascalcitoningene-relatedpeptide(CGRP)aredownregulatedduringdiabeticwoundhealing,corticotropinreleasingfactor(CRF),α-melanocorticotropinreleasinghormone(α-MSH),andneurotensin(NT)areupregulated,contributingtodelayedhealing.