Emerging roles of keratinocytes in nociceptive transduction and regulation

Abstract

Keratinocytes are the predominant block-building cells in the epidermis. Emerging evidence has elucidated the roles of keratinocytes in a wide range of pathophysiological processes including cutaneous nociception, pruritus, and inflammation. Intraepidermal free nerve endings are entirely enwrapped within the gutters of keratinocyte cytoplasm and form en passant synaptic-like contacts with keratinocytes. Keratinocytes can detect thermal, mechanical, and chemical stimuli through transient receptor potential ion channels and other sensory receptors. The activated keratinocytes elicit calcium influx and release ATP, which binds to P2 receptors on free nerve endings and excites sensory neurons. This process is modulated by the endogenous opioid system and endothelin. Keratinocytes also express neurotransmitter receptors of adrenaline, acetylcholine, glutamate, and γ-aminobutyric acid, which are involved in regulating the activation and migration, of keratinocytes. Furthermore, keratinocytes serve as both sources and targets of neurotrophic factors, pro-inflammatory cytokines, and neuropeptides. The autocrine and/or paracrine mechanisms of these mediators create a bidirectional feedback loop that amplifies neuroinflammation and contributes to peripheral sensitization.

Keywords: free nerve ending; keratinocyte; neuroinflammation; neuropeptide; neurotransmitter; peripheral sensitization.

FIGURE 1

Anatomical relationship between keratinocytes and sensory nerve endings. FNE, free nerve ending; DRG, dorsal root ganglion. Epidermis is divided into four layers: stratum basale, spinosum, granulosum, and corneum. Keratinocytes are the predominant cells in epidermis. The epidermis is highly innervated with intraepidermal free nerve endings, which are enwrapped but also ensheathed by keratinocyte cytoplasm. Their cell bodies are located in dorsal root ganglion, and are centrally projected to spinal cord dorsal horn. (By Figdraw).

FIGURE 2

Sensory receptors expressed on keratinocytes. TRPV, transient receptor potential vanilloid; TRPA, transient receptor potential ankyrin; TRPM, transient receptor potential melastatin; VGSC, voltage-gated sodium channel; VGCC, voltage-gated calcium channel; UV, ultraviolet irradiation. Human keratinocytes express TRPV1, TRPV3, TRPV4, and TRPA1, which are activated by thermal, cold, chemical, or ultraviolet stimuli, and mediate a calcium influx. TRPM8 and STIM1 are temperature-sensitive endoplasmic reticulum transmembrane channels expressed in human keratinocytes. STIM1 is coupled to its plasma membrane subunit, Orail, which also mediate a calcium influx. VGSC and VGCC have also been found in human keratinocytes. (By Figdraw).

FIGURE 3

Communications between keratinocytes and nociceptors. ATP, adenosine-5’-triphosphate; ET-1, endothelin-1; ET_A, endothelin-1 receptor A; ET_B, endothelin-1 receptor B; SP, substance P; CGRP, calcitonin gene-related peptide; TNF-α, tumor necrosis factor-α; IL, interleukin; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; NT, neurotrophin; GDNF, glia-derived neurotrophic factor. Neurotransmission between keratinocytes and sensory neurons is dependent on the release of ATP from keratinocytes and the activation of P2 receptors on nociceptors. Keratinocytes produce ET-1, which binds to ET_A on nociceptors to evoke pain. ET-1 also activates ET_B on keratinocytes, stimulating the release of β-endorphin, which binds to opioid receptors on nociceptors to relieve pain. Keratinocytes participate in neuroinflammation by producing neurotrophic factors and pro-inflammatory cytokines in response to neuropeptides released from nociceptors. Keratinocytes also express receptors of ATP, β-endorphin, neurotrophic factors, and pro-inflammatory cytokines, indicating the existence of paracrine and/or autocrine mechanisms. (By Figdraw).