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.

Nociceptive Sensory Fibers Drive Interleukin-23 Production from CD301b+ Dermal Dendritic Cells and Drive Protective Cutaneous Immunity

“…Expression of IL-23 and host defense could be inhibited by administering the CGRP peptide antagonist, CGRP 32-37 , and augmented by the addition of the CGRP agonist, CGRPα. Moreover, CGRPα rescued IL-23 responses in RTX-treated WT mice but did not rescue mice lacking CD301b + dDCs, indicating that CGRPα does not directly inhibit C. albicans proliferation or function indirectly through other cell types such as keratinocytes or fibroblasts (Roggenkamp et al, 2013). Thus, CGRPα acts downstream of TRPV1 + nociceptors but acts upstream of CD301b + dDCs.…”

Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin

“…In rodent skin nerves, SP is more abundant and its release induces PPE without inflammation. Although not painful when applied directly into the skin (Weidner et al, 2000) SP and CGRP are involved in sensitization of primary afferent nociceptors and the development of neuropathic pain after nerve lesion (Ambalavanar et al, 2006;Gradl et al, 2007;Jang et al, 2004;Lee and Kim, 2007), they regulate sweating (Schlereth et al 06) and they execute trophic function by stimulating fibroblast and keratinocyte proliferation (Peters et al, 2006;Roggenkamp et al, 2013). …”

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

“…For instance, after injury keratinocytes promote axon regeneration by secreting hydrogen peroxide (H 2 O 2 ) (15). On the other hand, cutaneous axons secrete neuropeptides to promote cutaneous homeostasis (16). Intriguingly, epithelial cells are highly susceptible to paclitaxelinduced damage, evident by the efficacy of paclitaxel in the treatment of carcinomas and by its skin-damaging effects in humans (10)…”