Neuro-cutaneous interactions in inflammatory, neuropathic, and metabolic skin diseases

ABSTRACT: The skin and nervous system engage in bidirectional communication. Disruption is implicated in inflammatory, neuropathic and metabolic disorders. To systematically review the structural and functional basis of skin-nerve interactions in health and disease, following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A systematic search of PubMed (inception to June 10, 2026) combined MeSH and free-text terms for skin innervation, sensory neurons, sympathetic nervous system, neuropeptides, neuroimmune regulation, and skin diseases. Manual supplementation via reference tracing and author searches improved recall. 86 original studies were ultimately included (45 from database search and 41 from manual supplementation). Key findings: (1) Keratinocytes, Merkel, Langerhans and melanocytes form synapse-like connections with nerve endings, establishing a "sensory epithelium." (2) Substance P activates mast cells via neurokinin 1 receptor/mas-related G protein-coupled receptor X2 (neurogenic inflammation); while calcitonin gene-related peptide inhibits dendritic cells (immune tolerance). (3) In atopic dermatitis, stress recruits basophils/eosinophils via sympathetic-beta-2 adrenergic receptor axis; in psoriasis, TRPV1+ neurons activate the interleukin-23/interleukin-17 axis via calcitonin gene-related peptide. (4) Stress induces sensory neurons to release miR-let-7b, exacerbating psoriasis via macrophage Toll-like receptor 7. (5) Postherpetic neuralgia: intraepidermal nerve fiber density < 650 neurites/mm2 correlates with central hyperexcitability ("phantom pain"). (6) Neurofibromatosis type 1 (RAS) and guanine nucleotide-binding protein G(q) subunit alpha (ANGPT2) mutations reveal mechanisms for tumors or vascular malformations. (7) Heat stress induces skin kallikrein-related peptidase 14 to reprogram hypothalamic LRRC7+ astrocytes via blood, forming a "heat memory" that leads to metabolic disorders (reversed by vitamin A). Substance P/neurokinin 1 receptor, sensory nerve-calcitonin gene-related peptide-interleukin-23, sympathetic-beta-2 adrenergic receptor-basophil/eosinophil, and skin-hypothalamic circuits are key translational pathways. Targeting these (neurokinin 1 receptor antagonists, β-blockers, anti-calcitonin gene-related peptide antibodies, and vitamin A) offers therapeutic opportunities for inflammatory skin diseases, neuropathic itch/pain and stress-related metabolic disorders.