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.

Cutaneous‐immuno‐neuro‐endocrine (CINE) system: A complex enterprise transforming skin into a super organ

“…17,81,96 The receptors for these neuromediators are expressed by a variety of native skin cells as well as immune cells. 53 Various events taking place during physiologic and pathologic cutaneous states provide hints of close functional relationship between CSANs and CICs. Native skin cells including KCs and endothelial cells and immune cells chiefly mast cells routinely release neuromediators under physiological circumstances but the effects are subtle.…”

“…Once stimulated, CSANs release more neuromediators that further activate more nerve fibres by recruiting inflammatory cells 17,81,96 . The receptors for these neuromediators are expressed by a variety of native skin cells as well as immune cells 53 …”

“…These KCs release neuropeptides such as SP, CGRP and NGF which trigger CSANs in an autocrine or paracrine fashion, and these activated CSANs in turn stimulate KCs to proliferate and secrete pro‐inflammatory cytokines and chemokines, which include interleukins (IL‐1α/β, IL‐3, IL‐4, IL‐6, IL‐7, IL‐8, IL‐10, IL‐12, IL‐15, IL‐16, IL‐18 and IL‐20), interferons (IFN‐α and IFN‐γ), TNF‐α, transforming growth factor‐(TGF)‐β and chemokines (CXCL‐1) 35,48–51 . Acetylcholine (Ach) produced by the KCs suppresses the functions of TLRs such as TLR2‐mediated cell migration and production of pro‐inflammatory cytokines and AMPs 23,52,53 . Further, these KCs express major histocompatibility complex (MHC) class II molecules as evident in studies of graft‐versus‐host disease.…”

Roles of TRPM channels in glioma

“… 59 Early in the disease, the release of various endogenous substances can affect TRP pathway function, leading to infection and disease progression (for example, the release of leukotriene B4 induces TRPV1 activation). 60 One of the most critical pathological processes is the development of cancer cells. More and more evidence has shown that changes in TRP channel expression levels play a crucial role in the occurrence and development of tumors, including proliferation, 61 migration, 62 invasion, 63 and other characteristics of glioma.…”

NMDA Receptors Regulate Oxidative Damage in Keratinocytes during Complex Regional Pain Syndrome in HaCaT Cells and Male Rats

“…The skin serves as the body's primary interface with the external environment and plays a pivotal role in defense and sensory perception. Keratinocytes are the predominant cell type within the epidermis and make a significant contribution to peripheral pain sensitization [12]. Using a chronic post-ischemia pain (CPIP) model to mimic CRPS in male rats, our team previously identified the involvement of keratinocytes and N-methyl-D-asparagic acid (NMDA) receptor subunit 2 B (NR2B) in both the peripheral and central sensitization of CRPS [13].…”