title: Epidermal nerve fibers modulate keratinocyte growth via neuropeptide signaling in an innervated skin model.
abstract: Atopic eczema is a chronic inflammatory skin disease characterized by cutaneous nerve fiber sprouting and epidermal hyperplasia, pointing to an involvement of the peripheral nervous system in cutaneous homeostasis. However, the interaction of sensory neurons and skin cells is poorly understood. Using an innervated skin model, we investigated the influence of sensory neurons on epidermal morphogenesis. Neurons induced the proliferation of keratinocytes, resulting in an increase in the epidermal thickness. Inhibition of calcitonin gene-related peptide (CGRP), but not substance P (SP) signaling, reversed this effect. Human CGRP enhanced keratinocyte proliferation and epidermal thickness in skin models, demonstrating a key role of CGRP in modulating epidermal morphogenesis, whereas SP had only a moderate effect. Innervated skin models composed of atopic skin cells showed increased neurite outgrowth, accompanied by elevated CGRP release. As atopic keratinocytes were sensitized to CGRP owing to higher expression levels of the CGRP receptor components, receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP), atopic innervated skin models displayed a thicker epidermis than did healthy controls. We conclude that neural CGRP controls local keratinocyte growth. Our results show that the crosstalk of the cutaneous peripheral nervous system and skin cells significantly influences epidermal morphogenesis and homeostasis in healthy and atopic skin.
authors.affiliation: Research and Development, Beiersdorf AG, Hamburg, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Roggenkamp
authors.forename: Sarah
authors.initials: S
authors.lastname: Köpnick
authors.forename: Franz
authors.initials: F
authors.lastname: Stäb
authors.forename: Horst
authors.initials: H
authors.lastname: Wenck
authors.forename: Martin
authors.initials: M
authors.lastname: Schmelz
authors.forename: Gitta
authors.initials: G
authors.lastname: Neufang
mesh_terms: D000328:Adult; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003876:Dermatitis, Atopic / Q000378:metabolism* / Q000503:physiopathology*; D020405:Dermis / Q000166:cytology / Q000294:innervation / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000294:innervation* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D008875:Middle Aged; D009479:Neuropeptides / Q000378:metabolism*; D009924:Organ Culture Techniques; D017933:Peripheral Nervous System / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D013373:Substance P / Q000378:metabolism; D055815:Young Adult
chemical_list: C117385:CIR1 protein, human; D009479:Neuropeptides; C545502:RAMP1 protein, human; D012333:RNA, Messenger; D058262:Receptor Activity-Modifying Protein 1; D018015:Receptors, Calcitonin Gene-Related Peptide; D012097:Repressor Proteins; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide