Altered Somatosensory Pathways

FIGURE 6.1 Overview of neurogenic inflammation.

CGRP predominantly induces arteriole vasodilation and stimulates the proliferation of keratinocytes and vascular endothelial cells via interaction with a CGRP receptor. It is one of the most potent vasodilators and generally mediates anti-inflammatory and neurotrophic action. However, under certain circumstances, CGRP increases the adhesion of neutrophils and monocytes, enhances neutrophil accumulation and edema formation, and promotes the release of TNF-a from mast cells, indicating its proinflammatory role. It inhibits the degradation of SP by neutral endopeptidase (NEP) and triggers SP release (8,10,16).

Moreover, there are about 30 other neurotransmitters identified in the skin, for example, NK A, neurotensin, vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, neuropeptide Y, somatostatin, gastrin-releasing hormone, β-endorphin, enkephalin, and galanin. There are excellent review papers on other neuropeptides in the skin elsewhere (8,10,30–34). Collectively, neural mediators from nociceptors promote (a) chemotaxis and activation of neutrophils, macrophages, and lymphocytes and degranulation of mast cells; (b) increased blood flow, vascular leakage, and edema; and (c) priming of dendritic cells for T cell differentiation (11).

Moreover, many cells with neuropeptide receptors also produce neuropeptide-degrading enzymes such as NEP or angiotensin-converting enzyme to limit the extent or duration of neurogenic inflammation (8,10).

The coordinated interaction between the peripheral nervous system and the immune system is mediated by different types of peripheral nerves and target cells in the skin such as keratinocytes, mast cells, endothelial cells, fibroblasts, and other immune cells (10,14). These interactions are implicated in cutaneous disease states such as urticaria, psoriasis, atopic dermatitis, hypersensitivity reactions, rosacea, UV-induced inflammation, and sensitive skin as well as normal homeostasis (8,10,16,19,29,33,35–41).

Taken together, neurogenic inflammation is a multidirectional and interactive cross talk between the peripheral nervous system, the immune system, and skin cells such as keratinocytes. Targeting neurogenic inflammation is a promising target of novel therapeutic approaches for sensitive skin.

The Role of Vanilloid Receptors in Sensitive Skin

Many subjects with sensitive skin report untoward sensory feelings such as pruritus, burning, and pain to changes in temperature (1). This phenomenon led to the notion that receptors and pathways that mediate both temperature sensation and sensory symptoms are implicated in the pathogenesis of sensitive skin. Moreover, the stinging test using capsaicin or lactic acid has been employed as a robust method to diagnose sensitive skin objectively (2,6,42).

Capsaicin, the main pungent ingredient of hot chili pepper, is a natural agonist of TRPV1. Since the successful cloning of TRPV1 in 1997 (43), significant progress has been made in the field of TRPV1 biology (8,22,44–46). Six related subfamilies (TRPV [vanilloid], TRP canonical, TRP melastatin, TRP polycystin, TRP mucolipin, and the TRP ankyrin groups) based on the amino acid sequence homology comprise mammalian TRP channels. TRP channels are composed of six putative transmembrane domains, a pore-forming loop between the fifth and sixth domains, and intracellular NH₂ and COOH termini that assemble as homo- or heterotetramers to form cation-permeable channels (22,47). TRPV1 forms cation channels with varying selectivity to diverse cations. For example, capsaicin-activated TRPV1 channels have roughly a 10:1 selectivity (permeability ratio) of Ca²⁺ over Na⁺, whereas heat-activated TRPV1 channels have a 4:1 selectivity (22,48). In addition to Ca²⁺ influx, Ca²⁺ release from internal stores, such as the Golgi apparatus, the endoplasmic reticulum, or the sarcoplasmic reticulum in muscle cells, contributes to changes in intracellular Ca²⁺ (22).

TRPV1 is a key molecular sensor and signaling integrator of thermal, chemical, and other sensory stimuli (49). TRPV1 is expressed on keratinocytes, fibroblasts, mast cells, endothelial cells, and sensory C and A-δ fibers (50–53). TRPV1 is a crucial contributor to pain, itch, and neurogenic inflammation (54–56). TRPV1 can be activated by low pH (<5.9), noxious heat (>43°C), and various chemicals such as adenosine triphosphate (ATP), anandamide, leukotriene B4, and resiniferatoxin (22) (Table 6.1; Figure 6.2). Long-term application of capsaicin causes TRPV1-mediated depletion of neuropeptides, leading to the desensitization of nerves (long-lasting refractory state unresponsive to further seemingly innocuous stimuli), and the amelioration of inflammatory responses (8,44).

The channel activity of TRPV1 can be markedly enhanced by low pH or inflammatory mediators via the activation of protein kinase A (PKA), PKC, PLC, and Ca²⁺/CaMKII pathways, leading to receptor sensitization, which lowers sensory perception thresholds (22,57–59). Pain sensation is augmented by acidic milieu during ischemia or inflammation. A-δ and C fiber neurons transduce extracellular protons via at least two different classes of cation-selective channels, TRPV1 and acid-sensing ion channels (ASICs) (60). On the contrary, TRPV1 can be inhibited by phosphorylation by cyclic adenosine monophosphate-dependent protein kinase (61).

The transmembrane influx of cations into the cytoplasm depolarizes the cells and elicits neuronal action potential propagation and muscle contraction. In nonexcitable cells such as keratinocytes and fibroblasts, membrane depolarization by TRPV1 leads to the stimulation of voltage-dependent channels and is associated with various physiological and pathological functions such as proliferation, differentiation, apoptosis, and inflammation (22,44,47,48). Previously, our group has identified the role of TRPV1 in intrinsic and extrinsic skin aging (induced by UV irradiation and heat) as well as UV-induced inflammation (62–66).

TABLE 6.1
Properties of TRPV1 Proteins

Source: Nilius, B., Owsianik, G., Voets, T., and Peters, J. A., Physiol Rev, 87, 165–217, 2007; Ramsey, I. S., Delling, M., and Clapham, D. E., Annu Rev Physiol, 68, 619–647, 2006; Veldhuis, N. A., Poole, D. P., Grace, M., McIntyre, P., and Bunnett, N. W., Pharmacol Rev, 67, 36–73, 2015.

Note: HETE: hydroxyeicosatetraenoic acid; HPETE: hydroperoxyeicosatetraenoic acid.

FIGURE 6.2 Overview of TRPV1.

Kueper et al. (2) showed that selective TRPV1 antagonist trans-4-tert-butylcyclohexanol could inhibit capsaicin-induced human TRPV1 (hTRPV1) activation in vitro in hTRPV1-overexpressing HEK293 cells and oocytes. Moreover, in a clinical study involving 30 women, the compound was effective in reducing capsaicin-induced burning in vivo (2). These findings strongly suggest that TRPV1 activation is important in the pathogenesis of sensitive skin and that TRPV1 antagonists can be used for the treatment of sensitive skin.

Novel Pathomechanism of Sensitive Skin

As previously summarized, sensitive skin is related to altered somatosensory systems, especially lowered pain threshold and enhanced pain induction elicited by neurogenic inflammation and TRPV1 activation. In addition, sensitive skin is associated with impaired skin barrier function and altered immune responsiveness (3,67). More recently, we employed an unbiased microarray analysis of skin samples obtained from subjects with sensitive or nonsensitive skin and identified the unexpected gene signature in sensitive skin, which is closely associated with the dysfunction of muscle contraction, metabolic homeostasis, and ion balance. These alterations may result in decreased synthesis of ATP and enhanced proton, leading to skin sensitivity (29,68).

Sensitive Skin Showed Decreased Expression of Muscle Contraction-Related Genes

Healthy volunteers with sensitive or nonsensitive skin were classified based on self-assessment questionnaires and a 10% lactic acid stinging test. Those with underlying skin diseases such as rosacea were excluded. Microarray analyses using the skin from volunteers revealed an unexpected and distinct gene expression signature that while 17 upregulated genes in sensitive skin are associated with the inflammatory and immune responses, 29 downregulated genes in sensitive skin represent muscle composition/contraction, carbohydrate/lipid metabolism, and ion transport/ionic balance (Tables 6.2 and 6.3).

Many downregulated genes are associated with muscle contraction and relaxation process as well as muscle structure. In human facial skin, striated muscle fibers are found in the reticular dermis and subcutis (69), along with smooth muscles accompanying the hair follicles (arrector pili). The sarcomere, a functional unit of muscle, is composed mainly of thick filaments (myosin, slow-type myosin-binding protein C), thin filaments (actin, troponin, alpha tropomyosin 1, nebulin), and elastic components (titin). In the presence of Ca²⁺ from sarcoplasmic reticulum and ATP, the myosin head binds to the actin that enables the thin filament to slide along the thick filament, allowing for the shortening of the sarcomere (cross-bridge cycling) (70). Actin-bound myosin cross bridges in sensitive skin had more compacted shape than those in nonsensitive skin, indicating more contracted cross-bridge state in sensitive skin tissues (Figure 6.3). Further supporting experiments demonstrated that the decreased expressions of muscle-related genes in sensitive skin were not due to either a sampling bias or differences in anatomical sites. Our results suggest that sensitive skin may be associated with abnormal muscle contraction/relaxation process (29).

Sensitive Skin Showed Dysfunction of Metabolic Homeostasis, Impaired Aerobic ATP Synthesis, and Abnormal Muscle Contraction/Relaxation

Muscle contraction and relaxation require ATP regeneration through metabolic pathways such as phosphocreatine, anaerobic glycolysis, or oxidative metabolism. Carbohydrate and fat are the principal substrates for oxidative metabolism (71). The genes related to carbohydrate (genes for enolase 3; glycogenin 2; phosphorylase, glycogen, muscle; phosphoenolpyruvate carboxykinase 1) and fat metabolism (genes for lipase E, hormone-sensitive type, perilipin 1, glycerol-3-phosphate acyltransferase, mitochondrial, fatty acid-binding protein 4, lipoprotein lipase) were downregulated in sensitive skin. Myoglobin and carbonic anhydrase III (muscle-specific), which are involved in aerobic ATP synthesis, were also downregulated in sensitive skin. Consequently, sensitive skin stored significantly less ATP than nonsensitive skin. Lack of ATP in muscles leads to abnormal muscle contraction/relaxation, fatigue, and pain (72). Thus, the lower expression of genes involved in metabolic pathways could result in a lower level of ATP, which may result in abnormal muscle contraction and pain in sensitive skin.

TABLE 6.2
Downregulated Genes in Human Sensitive Skin

Source:  J Dermatol Sci, 76, Kim, E. J., Lee, D. H., Kim, Y. K., Kim, M. K., Kim, J. Y., Lee, M. J. et al., Decreased ATP synthesis and lower pH may lead to abnormal muscle contraction and skin sensitivity in human skin, 214–221, Copyright (2014), with permission from Elsevier.

Note: S: sensitive skin; NS: nonsensitive skin; (−): − lactic acid; (+): + lactic acid.

TABLE 6.3
Upregulated Genes in Human Sensitive Skin

Source:  J Dermatol Sci, 76, Kim, E. J., Lee, D. H., Kim, Y. K., Kim, M. K., Kim, J. Y., Lee, M. J. et al., Decreased ATP synthesis and lower pH may lead to abnormal muscle contraction and skin sensitivity in human skin, 214–221, Copyright (2014), with permission from Elsevier.

Note: S: sensitive skin; NS: nonsensitive skin; (−): − lactic acid; (+): + lactic acid.

Enhanced Acidity May Cause Skin Sensitivity and Abnormal Muscle Contraction in Human Sensitive Skin

Muscle exposed to anaerobic state triggers the overproduction of carbon dioxide and H⁺, leading to enhanced acidity (73), which is known to elicit pain via TRPV1 and ASIC3 (43,74,75). Subjects with sensitive skin showed impaired pH homeostasis after lactic acid stimulation. The expressions of TRPV1, ASIC3, and CGRP were significantly induced in human sensitive skin. Moreover, rhabdomyosarcoma (RD) (skeletal muscle) cells treated with low pH showed significantly increased expressions of TRPV1, ASIC3, and CGRP. Finally, by using a well-established muscle contraction model in vitro, we confirmed that low pH could induce a state of abnormal muscle contraction, which was similar to that of sensitive skin. Collectively, our results suggest that sensitive skin may be associated with pain provocation through TRPV1, ASIC3, and CGRP due to impaired acidic homeostasis.

FIGURE 6.3 Actin-bound myosin cross bridges in sensitive skin. (Reprinted from J Dermatol Sci, 76, Kim, E. J., Lee, D. H., Kim, Y. K., Kim, M. K., Kim, J. Y., Lee, M. J. et al., Decreased ATP synthesis and lower pH may lead to abnormal muscle contraction and skin sensitivity in human skin, 214–221, Copyright (2014), with permission from Elsevier.)

ADIPOQ Mediates Sensitivity in Human Skin

Adiponectin, C1Q and collagen domain containing (ADIPOQ) is an adipocyte-derived adipokine with multiple salutary effects, such as antiapoptotic and anti-inflammatory activities (76). The expression of ADIPOQ and adiponectin receptor was markedly downregulated in sensitive skin. Adenosine monophosphate-activated protein kinase, a downstream regulator of glucose and lipid metabolism, was also downregulated in sensitive skin (77). Intriguingly, the transient knockdown of ADIPOQ in vitro recapitulated the distinct gene expression signature in human sensitive skin in vivo (29) and showed abnormal muscle contraction, and lower ATP concentration, lower pH, but greater expression of pain-related transcripts such as TRPV1, ASIC3, and CGRP than control small interfering ribonucleic acid-transfected cells. Conversely, the treatment of RD cells with ADIPOQ induced a substantial reduction in the expressions of pain-related transcripts, suggesting a potential therapeutic role of ADIPOQ supplementation in sensitive skin.

FIGURE 6.4 A schematic model of putative pathway from reduced adiponectin to sensitive skin.

The disruption of metabolic homeostasis can cause variable diseases such as obesity, diabetes, and metabolic syndrome, which are closely associated with reduced ADIPOQ production (78). Little is known about the relationship between sensitive skin and metabolic disorders. Sensitive skin is also linked to ADIPOQ deficiency (Figure 6.4), and reduced ADIPOQ in sensitive skin may influence metabolic disorders or vice versa. Further preclinical and clinical studies are required to confirm its role in the treatment of sensitive skin in vivo.

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* Dong Hun Lee and Jin Ho Chung share senior authorship.

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