Chapter 102. Neurobiology of the Skin

This chapter discusses the structural basis and the specific molecules involved in the interactions between the skin and different portions of the nervous system.

The peripheral nervous system provides essential information to the rest of body during injury of “danger signals” such as parasites, UV radiation, toxins, allergens, pH changes, or “stress”. This information can be modulated at various levels including the brain, spinal cord, dorsal root ganglia (DRG), peripheral sensory nerve endings, autonomic nerves and neurons, etc; and through specialized structures like Pacini bodies or specialized cells such as Merkel cells. This closely woven group of structures and their molecules are ultimately and critically involved in normal cutaneous biology and skin diseases (eTable 102-0.1). In conjunction with the spinal cord and the brain, peripheral sensory nerves have afferent functions; their endings detect physical stimuli such as touch, heat or cold, and chemical mediators into the skin from nerve endings and also have efferent functions in the skin. (eFig. 102-0.1). These sensory nerves critically contribute to skin development before birth and to protection and homeostasis after birth. In addition, autonomic nerves modulate both physiological and pathophysiological functions as part of the stress response to external or endogenous stimuli, and form a vital link communicating with the vascular, endocrine, and immune systems (eTable 102-0.1).

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Peripheral Nerves

Sensory as well as autonomic (in the skin predominantly cholinergic sympathetic) nerves influence a variety of physiologic and pathophysiologic functions of the skin such as embryogenesis, vasoconstriction, vasodilation, body temperature, erector pili movement, regulation of the function of the pilosebaceous unit, sensing physical, chemical and biological stimuli on the skin surface; modulating epidermal barrier function, cell secretion, cell growth and differentiation, cell nutrition and apoptosis, nerve growth, inflammation, immune defense, and wound healing, respectively (eTable 102-0.1).

In unstimulated cutaneous nerves, neuromediators are stored in cytoplasmic vesicles. On direct or indirect activation through physical, mechanical, electrical, chemical or biologic or endogenous inflammatory processes lipids, cytokines or neurotrophins (NT), a significant increase of regulatory neuropeptides, or oxygen products can be detected at the site of inflammation within seconds to hours. Thus, mediators derived from sensory or autonomic nerves may play an important regulatory role in the skin under many physiologic and pathophysiologic conditions. However, in addition to neuroimmunomodulation in the periphery, a subtle and complex communication network also exists between the spinal cord, the central nervous system (CNS), and the immunoendocrine system that also modulates skin function. In addition, neuropeptides and NTs can be upregulated and released by nonneuronal cells under certain circumstances that may amplify or counterregulate the neurogenic stimulus. While certain neuropeptides [e.g., substance P (SP)] exert clear-cut proinflammatory effects during inflammation, others such as calcitonin-gene-related protein (CGRP) may be acutely released to induce vasodilatation (proinflammatory), but in addition counterregulate inflammatory responses like antigen presentation and immunosuppression in order to reestablish skin homeostasis at the later stage of inflammation.

The skin expresses a variety of receptors for these neuromediators, such as G protein-coupled receptors, ion channels and certain cytokine receptors (see Tables 102-1 and 102-2). This neuromediator–receptor interaction is controlled by endopeptidases [neutral endopeptidase (NEP), angiotensin-converting enzyme (ACE), endothelin-converting enzyme (ECE)], which terminate neuropeptide-induced inflammatory or immune responses.1–3 A close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory peptidases is critical to maintain or reestablish tissue integrity and regulating pathophysiologic conditions in the skin. Ion channels are promiscuous and can be activated by physical stimuli (heat, cold), chemicals (e.g., capsaicin, menthol, protons) as well as lipid metabolites like prostaglandins. Activation of ion channels by cannabinoids (CB) has been also recently described.

From this background, it is clear that a better cellular and molecular understanding of the complex skin–nervous system interactions opens an avenue for future therapeutic approaches to skin disease.

Taken as a whole, present information clearly indicates a crucial role for the neuronal skin network in influencing a variety of physiologic and pathophysiologic functions such as host defense, inflammation, pruritus, pain, burning, wound healing, and probably cancer (e.g., by modulating angiogenesis).

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Brain–Skin Axis

The CNS proper is connected to skin either directly via efferent nerves or CNS-derived mediators, or indirectly via the adrenal glands or immune cells.1 Cutaneous nerves also respond to internal stimuli from the circulation (e.g., pH changes, osmotic changes, bradykinin, cytokines) or the skin itself and to emotions (internal trigger factors).2 Under normal circumstances, the sensory and the autonomic nervous systems modulate important biologic functions such as body temperature, blood flow, and cell growth. Mechanically induced nerve impulses transmit information such as pressure to the CNS. Chemical- or heat-responsive afferent nerve fibers are involved in recognizing dangerous signals. Thus, normally the innervated skin is a crucial barrier in protecting the body from danger from the external environment. This is also supported by the finding that not only the dermis but also the epidermis is highly innervated.4 Interactions between the central and peripheral nervous system have been implicated to play a role in thermoregulation,1,5 the pathophysiology of various skin diseases such as psoriasis,6–8 atopic dermatitis,9 acne,10 wound healing,11 as well as hair loss and regrowth.12–14

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Spinal Cord

Our knowledge about the involvement of the spinal cord in regulating specific chronic pain sensations in human skin, its role in modulating pruritus, or modulating inflammatory stimuli transduced from the periphery to the brain is very limited. We know that μ-opioids such as morphine can induce pruritus while being analgesic when injected intrathecally. In contrast, κ-opioids exert antipruritic effects, probably by the inhibition of the μ-opioid receptor. These results strongly indicate a role of opioids in the regulation of pain and pruritus on the spinal cord level. Moreover, gastrin-releasing peptide (bombesin) released to the central nerve endings in the spinal cord activates the gastrin-releasing peptide receptor (GRPR) on postsynaptic spinal neurons, thereby regulating selectively itch transduction but not pain.15,16 Together, these data implicate the spinal cord as an important regulator of skin–nervous system interactions as observed during inflammation, pruritic diseases, and pain, and may be a target for future therapies.

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Sensory Nerves

Most nerve fibers are found in the middermis and the papillary dermis. Region-specific differences can be observed with respect to the mucocutaneous border, glabrous skin, and hairy skin.17 In the epidermis, sensory nerves are linked to keratinocytes, melanocytes, Langerhans cells (LC), and Merkel cells. Cutaneous nerve fibers are principally sensory, with an additional complement of autonomic nerve fibers.18,19 In contrast to sensory nerves, autonomic nerves never innervate the epidermis in mammals. Sensory nerves innervate the epidermis and dermis as well as the subcutaneous fatty tissue20–22 (see eFig. 102-0.1).

Sensory nerves are categorized into two groups: (1) the epidermal and (2) the dermal skin nerve organs. The epidermal skin nerve organs consist of free nerve endings or nerve organs (e.g., Merkel cells). In the dermis, there are free sensory nerve endings, the hair nervous network (Pinkus discs), and the encapsulated endings [Ruffini, Meissner, Krause, and Vater–Pacini (vibration) corpuscles, and mucocutaneous end organ]. These can be subdivided into four groups: (1) A-α fibers (12–22 nm) are highly myelinated, show a fast conduction velocity (70–120 m/second), and are associated with muscular spindles and tendon organs. (2) A-β fibers are moderately myelinated (6–12 μm) and innervate touch receptors. (3) A-δ fibers have a thin myelin sheath (1–5 μm), show an intermediate conduction velocity (4–30 m/second), and are generally polymodal. (4) The slow-conducting C fibers (0.5–2.0 m/second) are unmyelinated and thin (0.2–1.5 μm) (nociceptors). A-β and A-δ fibers are mostly mechanically sensitive afferents (type I) localized on hairy and glabrous skin and show a long latency to heat. A subpopulation of A-δ fibers on hairy skin are mechanically insensitive (type II). A-δ fibers constitute approximately 80% of primary sensory nerves sprouting from DRG, whereas C fibers make up approximately 20% of the primary afferents.23,24

C-fibers are either polymodal nociceptors, which can respond to chemical (c+), temperature changes (h+) or mechanical (m+) stimuli, or more specialized, which only respond to a combination (C-c+h+m−) or a single stimulus (C-c−h−m+). Among human peripheral nerves, 45% of the cutaneous afferent nerves belong to a subtype of sensory nerves that are both mechano- and heat-responsive C-fibers (C-c−m+h+).25 However, 13% of these nerves are only mechanosensitive (C-m+), 6% only heat sensitive (C-h+), 24% are neither heat nor mechanoresponsive (C-m−h−), and approximately 12% are of sympathetic (cholinergic) origin. Fifty-eight percent of C-m+h+ respond to mustard oil, whereas 30% of C-m+ or (C-m−h−) do so indicating the existence of chemosensitive fibers among the other subtypes.25

Sensory nerves percept cutaneous stimuli such as warmth, cold, or touch. The nerves for warmth are predominantly unmyelinated C-fibers, a subpopulation of A-δ fibers respond to gentle cooling, whereas selective C-fibers become activated during noxious cold. Many subtypes of cells respond to touch and play an important role in mechanically induced pain. Thus, our body system has designed less selective as well as highly specialized nociceptors in order to guarantee body integrity and survival.26

A specific receptor distribution on these different sensory nerve subtypes appears to be important for the various functions (temperature, chemical, mechanical) and the sensations, which may derive thereof (prickling, stinging, burning, pain, itch). For example, mechanoreceptors exclusively express the T-type calcium channel Ca(v)3.2 in the dorsal root ganglion of D-hair receptors. The sodium channels Nav1.8 (SNS/PN3) and Nav1.9 (SNS/SNS2) are expressed by both peptidergic as well as nonpeptidergic IB4+ (isolectin B4 from Griffonia simplicifolia) neurons and have been shown to be critically involved in certain subtypes of pain.27 Only certain small-diameter primary afferents express the transient receptor potential vanilloid-1 (TRPV1) receptor which is critically involved in heat sensation.28 Only nonpeptidergic (poor peptidergic) sensory fibers express the purinergic P2×3 receptor. Exogenous factors like trauma, UV-radiation, temperature changes, microbial agents, toxins, or allergens, as well as endogenous inflammatory triggers such as pH changes or stress hormone responses are able to stimulate the activation and/or sensitization of certain sensory nerves. The cellular events that transmit a stimulus (e.g., UV radiation) to a certain response (burning pain) via activation of a certain pathway (activation of pain fibers but not itch fibers and vice versa) are only poorly understood.29,30

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Autonomic Nerves

Compared to sensory nerves, autonomic nerves represent only a minority of cutaneous nerve fibers. In human skin, autonomic nerve fibers are derived almost completely from sympathetic (cholinergic) and rarely from parasympathetic (also cholinergic) neurons.31 The distribution of autonomic nerves is restricted to the dermis, where they innervate blood vessels, arteriovenous anastomoses, lymphatic vessels, erector pili muscles, eccrine glands, apocrine glands, and hair follicles.32

Postganglionic autonomic nerves in the skin predominantly generate acetylcholine, although observations have revealed an additional role for neuropeptides. For example, neuropeptide Y (NPY) and atrial natriuretic peptide33 are expressed solely by autonomic nerve fibers.34

The cutaneous autonomic nervous system adjusts sweat gland function, thereby regulating body temperature, and modulates water and electrolyte balance in various organs. Under pathophysiologic conditions, autonomic nerves are involved in hyperhidrosis or hypohidrosis, congenital sensory neuropathy type IV, progressive segmental hypohidrosis, diabetic neuropathy, syringomyelia, lepra, and dysfunction after sympathectomy.35–38

Autonomic nerves exert their effects mainly by releasing classical neurotransmitters (noradrenaline, acetylcholine) or—to a lesser extent—certain neuropeptides like vasoactive intestinal peptide (VIP). In contrast, primary afferent (sensory) nerves release different classes of molecules such as neuropeptides, prostanoids, or nitric oxide (NO).1

Autonomic nerve fibers are crucially involved in the regulation of vascular effects in the skin. Sympathetic nerve fibers release noradrenalin and/or NPY to innervate arterioles, arteriovenous anastomoses, and venous sinusoids, which results in vasoconstriction, whereas parasympathetic nerves mediate vasodilation through activation of venous sinusoids by the release of acetylcholine and vasoactive intestinal peptide (VIP)/peptide histidine methionine39–42 (eTable 102-0.1 and Table 102-1). Of note, C-fiber nociceptors can develop responsiveness to adrenergic neurotransmitters by upregulating the corresponding receptors during trauma or inflammation. Thus, the sensory and the autonomic nervous systems communicate and interact in disease on the molecular level.

Small arteries, arterioles, and the arteriovenous anastomoses are richly supplied with noradrenergic nerves.43 Previous studies suggested that this system is cholinergic and involves a cotransmitter, possibly VIP.44 Cholinergic sympathetic nerves are also known to stimulate eccrine sweat glands via muscarinic receptors,31 whereas higher concentrations of acetylcholine induce an axon-reflex flare mediated via nicotinic receptors. In the vasoconstrictor system, the transmitter appears to be norepinephrine along with one or more cotransmitters. The best-characterized sympathetic cotransmitters that participate in the regulation of blood flow include adenosine triphosphate45 and NPY.46

Interestingly, even without intact sensory or autonomic function the skin reveals a nonneurogenic vasodilator and nonneurogenic vasoconstriction response. The mechanisms for the nonneurogenic vasodilator and vasoconstrictor components of the response to direct cooling are poorly understood but may involve several pathways including cholinergic stimulation, NO and neuropeptides.5,47

As outlined above, many subtypes of nerve fibers exist to cover the multiple functions of the skin nervous system to maintain or reestablish body integrity. This chapter focuses on the role of neuropeptides, TRP channels, and cytokines in the skin (Table 102-1).

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Skin Neuropeptides and Neuropeptide Receptors

Classically, neuropeptides range from as few as 4 to more than 40 amino acids. Because they are released by nerve endings and modulate various biologic functions, they were originally defined as neuropeptides. Later, these molecules were also found to be generated by nonneuronal cells (e.g., epithelial cells and immune cells). Therefore, the designation regulatory peptide may be more appropriate.48 These peptides mainly activate members of the G protein-coupled receptor superfamily with seven transmembrane domains. To date more than 20 neuropeptides, including SP, neurokinin A (NKA), neurotensin, CGRP, VIP, pituitary adenylate cyclase-activating polypeptide (PACAP), peptide histidine-isoleucinamide, NPY, somatostatin (SST), dynorphin, β-endorphin, enkephalin, galanin, secretoneurin, melanocyte-stimulating hormone (MSH), thyroid-stimulating hormone (TSH), or corticotropin-releasing hormone (CRH), have been detected in the skin.1,2,49 Table 102-1 lists the neuropeptides, ion channels, and other molecules like NO involved in pruritus, pain, and inflammation. eFigure 102-0.1 and Fig. 102-1 depict the basic concepts and knowledge concerning these neuropeptides.

Various neuropeptides are produced and released by a subpopulation of unmyelinated afferent neurons (C fibers) known as C-polymodal nociceptors. In addition, it has been shown that cutaneous cells themselves, such as keratinocytes, microvascular endothelial cells, Merkel cells, fibroblasts, and leukocytes, are capable of releasing regulatory peptides under physiologic or pathophysiologic circumstances.

In the skin, nerves are necessarily closely linked to the vascular system. Dermal blood vessels are tightly associated with sensory and autonomic nerve fibers, they also synthesize neuropeptides and they express receptors for neuropeptides. Arterial sections of arteriovenous anastomoses, precapillary sphincters of metarterioles, arteries, and capillaries appear to be the most intensely innervated regions. Large increases in skin blood flow provide the necessary augmentation of convective heat loss during environmental heat exposure and/or exercise, and the reflex cutaneous vasoconstriction is key to preventing excessive heat dissipation during cold exposure. Sensory nerves are important for vasodilation and neuropeptides from sympathetic neurons such as NPY mediate vasoconstriction, which supports an important role for neuropeptides in thermoregulation, blood flow during inflammation or tumorigenesis, as well as activation of endothelial cells and smooth muscle cells. Both endothelial cells and smooth muscle cells respond to neuronal modulation in inflammatory diseases such as atopic dermatitis and rosacea and during host defense, neovascularization, and wound healing. Sensory as well as autonomic nerves modulate the function of sweat glands, sebaceous glands, apocrine glands, and the pilosebaceous unit. In the following, we emphasize the biological role of certain neuromediators and neurohormones in more detail.

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Tachykinins

 In the skin, tachykinin-immunoreactive sensory nerves are often associated with dermal blood vessels, mast cells, hair follicles, or epidermal cells (Fig. 102-1).50 Increased epidermal substance P (SP)-immunoreactive nerve fibers have been observed in certain inflammatory human skin diseases such as psoriasis, atopic dermatitis, and contact dermatitis.51,52 Moreover, several immune cells are capable of generating SP induced by stress, inflammation, or infection.53–55 For example, SP appears to be involved in keratinocyte/antigen-presenting cell interactions during chronic stress,54 T cell regulation,56 natural killer cell activation,57 innate host defense,58 HIV-associated psoriasis,53,59 wound healing,60 murine hair follicle apoptosis,61 genital herpes infection,62 and immunosurveillance during experimentally induced tumor growth (murine melanoma).63 SP may be also involved in inflammation and host responses of the CNS64 as well as transmitting sensory signals (neurogenic inflammation, pain, pruritus) to the CNS48,65. In addition, in a murine disease model, the NK1 receptor was recently shown to play an important role in the development of airway inflammation and hyperresponsiveness.66

 During wound healing, SP may promote the healing process by affecting the expression of both epidermal growth factor and epidermal growth factor receptor in the granulation tissues as demonstrated in a rat model.67 In addition, keratinocyte nerve growth factor (NGF) is induced by sensory nerve-derived neuropeptides such as SP and neurokinin A (NKA).68 Finally, SP may modulate cutaneous inflammatory responses by upregulation of cell adhesion molecule expression on keratinocytes.69

 In cultured normal human fibroblasts, a moderate amount of preprotachykinin-A was found, which was significantly upregulated by exogenous SP. Accordingly, SP was found to promote human fibroblast chemotaxis in a dose-dependent manner.70 The effects of SP on both fibroblast proliferation and transforming growth factor-β1 (TGF-β1) mRNA expression could be antagonized by a selective NK1R antagonist, suggesting that SP may play an important role in phenotype changes of fibroblast proliferation. In cultured rheumatoid fibroblast-like synoviocytes, SP enhances cytokine-induced VCAM-1 expression in a dose-dependent manner, probably via NK1R activation.

 Previous studies using the tachykinin NK1R antagonist, SR140333, have indicated that cutaneous edema can be mediated by NK1Rs and is independent of histamine effects.71 This finding is supported by experiments using NK1R knockout mice, which showed that intradermally injected SP, NK1R agonists (GR-73632), and the mast cell-degranulating agent, compound 48/80, induced dose-dependent cutaneous edema in wild-type mice and this did not occur in knockout mice.72 Despite of its disappointing role in pain, the NK1R antagonist aprepitant (Emend®) has been shown to play an important role to block chemotherapy-induced emesis, as well as pruritus in patients with Sezary-syndrome, solid tumors, or chronic pruritus.73–75

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Vasoactive Intestinal Peptide

 In the skin, VIP-like immunoreactivity was detected in nerve fibers associated with dermal vessels, glands such as sweat, apocrine, and Meibomian glands, hair follicles, and Merkel cells. VIP immunoreactivity was less abundant than SP immunoreactivity in the epidermal layer.76,77 VIP-staining fibers can be also found in close anatomical connection to mast cells.78–80,1,29,52 In the skin, VIP regulates temperature homeostasis and sweat production.81–85 VIP is also involved in neurogenic inflammation possibly through histamine release from mast cells, inducing bradykinin-mediated edema86,87 as well as stimulating cytokine release and growth factor release from keratinocytes.88 VIP may also play a role during infection. For example, antibodies against VIP were found in patients with HIV and were more prevalent in asymptomatic carriers and their titer correlated with disease progression.89

 VIP is involved in neuro-immunomodulation.90 This cytokine-like peptide exerts a broad spectrum of anti-inflammatory effects in mammals including humans.91 In murine T cells, VIP has the capacity to modulate CD4+CD25+ Foxp3-expressing regulatory T cells in vivo. Application of VIP into T cell receptor transgenic mice resulted in the expansion of T cells that inhibited the responder T cell proliferation, increased the level of CD4+CD25+ Treg cells, inhibited delayed-type hypersensitivity in T cell receptor-transgenic (TCR-Tg) hosts, and prevented graft-versus-host disease in vivo.92

 In macrophages, VIP and PACAP protect mice from lethal endotoxemia through the inhibition of TNF-α and interleukin-6 (IL-6) suggesting a protective role of both neuropeptides in innate immunity93 by downregulating TNF-α production.94 VIP is also involved in modulating innate immunity by downregulating toll-like receptor 4 (TLR4) expression and TLR4-mediated chemokine generation (CCL2, CXCL8).95

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Pituitary Adenylate Cyclase Activating Polypeptide

 PACAP is present in sensory and autonomic nerve fibers of DRG, the spinal cord and the adrenal glands suggesting involvement in sensory and nociceptive pathways.96,97 Moreover, PACAP-immunoreactive fibers are sensitive to capsaicin.97 In various organs of rodents and humans, PACAP displays neuroprotective, regenerative, and immunomodulatory functions. In severe combined immunodeficiency (SCID) mice, CD4+ T cells appear to induce PACAP gene expression, suggesting a regulatory role of immune cells on PACAP-induced immunomodulation and nerve regeneration.98

 In the skin, PACAP was detected in sensory nerve fibers99,100 coexisting with VIP, SP or CGRP, respectively, all of which may play an important role in inflammatory skin diseases like psoriasis, urticaria, or atopic dermatitis,101 The distribution of PACAP-3899,100 and the presence of the high-affinity PACAP1-receptor (PAC1R)99 was described in normal and inflamed human skin. The concentration of PACAP-38 appears to be enhanced in lesional skin of psoriasis patients.99 Moreover, the peptide level was significantly lower in nonlesional psoriatic skin than in lesional psoriatic skin, but was about twice as much as in normal human skin. Interestingly, immunoreactivity was significantly increased at the dermal–epidermal border in psoriasis99 around hair follicles and close to sweat glands of normal skin. In contrast, no significant increase of positive nerve fibers was observed around blood vessels. PACAP appears to be involved in cutaneous inflammation, for example, by releasing histamine from mast cells.100 PACAP modulates the function of blood vessels,102–106 T cells,90 or macrophages.197 PACAP appears to be an important vasoregulator in human skin in vivo.84,107

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Calcitonin Gene-Related Peptide and Receptors

 CGRP is one of the most prominent neuropeptides in the skin and often colocalized with either SP or SST (Fig. 102-1).108,109 CGRP-immunoreactive nerves are often associated with mast cells,110 Merkel cells,111 melanocytes,112 keratinocytes, and LC113,114 which are stimulated under inflammatory conditions.115 In LC, CGRP inhibits antigen-presentation capacities of the immune cells. CGRP-immunoreactivity was detected in association with smooth muscle cells and blood vessels.116,117 CGRP has also potent vasoactive effects,118 and can increase keratinocyte proliferation112 or cytokine release. CGRP and SP also upregulated IL-8R mRNA expression but not IL-8 production in HaCaT cells.119 CGRP also mediates anti-inflammatory and neurotrophic effects.120 CGRP modulates macrophages,121 neutrophils,122 and dermal microvascular endothelial cells.109,123 CGRP is one of the most potent vasodilatatory mediators on small and large vessels124–127 and potentiates microvascular permeability and edema formation caused by SP or NKA. CGRP and endothelin are colocalized in endothelial cells suggesting autoregulatory mechanisms for blood flow.128

 CGRP may be regulated by UV-mediated responses because irradiation of the skin decreased CGRP mRNA expression in DRG.129 CGRP also induces melanocyte proliferation by upregulating melanogenesis and enhances melanocyte dendricity by inducing keratinocyte-derived melanotropic factors130 indicating a modulatory role of CGRP for epidermal melanocyte function. Therapeutically, CGRP receptor antagonists like olcegepant or telcagepant have been proven to be effective for the treatment of migraine indicating a role of this receptor in neurogenic diseases and neurogenic inflammation.131,132

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Somatostatin and Receptors

 SST is described as an inhibitor of exocrine and endocrine secretion from a variety of tissues, and a predominantly antiproliferative molecule with tumor-suppressive properties that are mediated by tyrosine phosphatases.133,134 It also inhibits proliferation of T cells135 and leukocyte recruitment during the initial phase of inflammation.136 SST is released by sensory nerves which may have an immunosuppressive role in some basophil-dependent hypersensitivity reactions.137 However, SST may also stimulate histamine release from human skin mast cells138 and may be involved in the pathophysiology of atopic dermatitis and mastocytosis.139–141

 Somatostatin receptors were detected in inflammatory lesions of patients suffering from rheumatoid arthritis, sarcoidosis, and granulomatosis with polyangiitis (Wegener's).142,143 Treatment with octreotide of two patients with sarcoid granulomas143 or systemic sclerosis144 resulted in clinical improvement suggesting a role of SST analogs in the treatment of granulomatous diseases.

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Opioids and Proopiomelanocortin Peptides

 Opioids are peptidergic neurotransmitters with antinociceptive capacities and are divided into three classes: (1) endorphins, (2) enkephalins, and (3) dynorphins. Opioid receptors (OR) are classified into three subtypes: (1) μ-, (2) κ- and (3) δ- (Table 102-1).

 In the skin, POMC peptides are expressed by melanocytes, keratinocytes, adnexal epithelial cells, sebocytes, microvascular endothelial cells, LCs, mast cells, and fibroblasts as well as by immune cells such as monocytes, dendritic cells, and macrophages.145 The skin and in particular the hair follicle seems to generate the whole armada of mediators generated by the hypothalamic-pituitary-adrenal (HPA) axis such as β-endorphin, MSH, ACTH, CRH, their receptors [μ-opioid receptor (μOR), MC-R, ACTH-R, CRH-R], and enzymes regulating POMC peptide function like PC1, and PC2.146

 β-Endorphin can be generated in human keratinocytes via activation of the μOR by ultraviolet radiation. In human melanocytes, β-endorphin has melanogenic, mitogenic, and dendritogenic effects in vitro, and expresses μOR.147 Accordingly, human hair follicle melanocytes also express β-endorphin and μOR, especially in glycoprotein-100-positive cells, suggesting a role of hair growth in an autocrine fashion. Thus, β-endorphin may be involved in pigmentation and hair growth. Recent findings indicate that β-endorphin also has a role in cutaneous neurogenic inflammation and analgesia via endothelin-1 (ET-1) activation of keratinocytes leading to the release of β-endorphin.148 Similarly, CB seem to regulate the release of β-endorphin from keratinocytes thereby modulating nociception in the skin.149 These findings clearly indicate a crucial role for epidermally derived β-endorphin in cutaneous nociception. β-Endorphin may be also involved in the pathophysiology of acne150 and atopic dermatitis.151,152

 Increased amounts of enkephalins were reported in lesional skin of psoriasis patients and were reduced in parallel with the clinical improvement induced by a topical vitamin D analog and a corticosteroid. Application of [met]-enkephalin induced a flare reaction in the skin that was by pretreatment with antihistamine, suggesting both histamine and histamine-independent involvement of enkephalins in neurogenic inflammation.153 [Met]-enkephalin induces infiltration of dermal lymphocytes, monocytes, and macrophages, and enkephalins protect against tissue damage caused by hypoxia, and inhibit differentiation and proliferation of keratinocytes.153,154 Thus, because enkephalins can modulate epidermal differentiation and inflammatory processes, these findings indicate that enkephalins may play a role in the pathogenesis of psoriasis.155

 Dynorphin is a neurotransmitter as well as an immunomodulatory molecule. Immunohistochemical studies in animals revealed the presence of dynorphin A predominantly in sympathetic axons innervating the cutaneous venous bed, but also in sensory nerve fibers, Merkel cells, and immune cells within the inflamed tissue.156,157 The discovery of inhibited nociception during inflammation by endogenous opioids increased interest in this neuromodulatory peptide. Dynorphin may exert antipruritic effects via activation of κOR in the spinal cord.1 Finally, dynorphin modulates keratinocyte migration in wound healing.151

 Systemic158 as well as topical treatment159 with a μ-opioid receptor antagonist (systemically: naltrexone 50–100 mg; naltrexone cream 1%) has been shown to be effective for the therapy of atopic dermatitis and chronic eczema-associated pruritus.

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Melanocyte-Stimulating Hormones

 Melanocortins (MCs), adrenocorticotropin (ACTH), and melanocyte-stimulating hormones (α-, β-, γ-MSH) are derived from the precursor POMC after posttranslational processing by members of the prohormone convertase (PC) family.49 Initially, MCs were characterized as regulators of pigmentation and cortisol production but there is increasing evidence for a role of MSH in food intake, sexual behavior, exocrine gland function, and inflammation.49,160 MCs exert their effects by binding to melanocortin receptors (MC-R), which belong to the family of G-protein coupled receptors. The MC-R family includes five members (MC1-R to MC5-R), which display overlapping specificities and usually bind several MCs. Only MC2-R shows a strong selectivity for ACTH.161 MC-Rs, especially MC1-R, are more widely expressed than originally believed and occur not only on melanocytic and neuronal cells but also in various cells of the immune system, epithelial cells, endothelial cells, and fibroblasts49 (Table 102-1).

 The role of melanocortins in skin pigmentation is well established.162 Patients with POMC null mutations have recently been described to display the red hair and fair skin phenotype.163 Moreover, the inductive effects of UV light on melanocortins and MC1-R expression in epidermal cells indicates that tanning is apparently dependent on the activation of the MC system in the skin.164 α-MSH also stimulates follicular melanogenesis by preferentially increasing the synthesis of eumelanin over pheomelanin via the stimulation of tyrosinase activity.165 Furthermore, α-MSH reduces UVB-induced DNA damage not only through the induction of pigmentation but also by modulating the function of DNA repair molecules by inducing nuclear translocation of XPA, a critical factor controlling nucleotide excision repair signaling pathways.166 Recently a novel aspect involving the cytoprotective and antioxidative effect of α-MSH has been detected. Accordingly, α-MSH was found to prevent the UVB mediated suppression of Nrf transcription factors, which are crucially involved in the protection against oxidative stress.172 ACTH and α-MSH also may play a role in hair growth146 and the regulation of sebaceous gland function.167

 The best-investigated MSH in the skin is α-melanocyte-stimulating hormone (α-MSH). It is a tridecapeptide also derived from the POMC gene, but maturated by posttranslational processing. α-MSH has been demonstrated to be involved in pigmentation. In addition, it is a potent anti-inflammatory mediator when administered systemically or locally. This effect is mediated by receptor-mediated modulation of immune responses and by affecting skin cells such as fibroblasts. It regulates nuclear factor-κB (NF-κB) activation, the expression of adhesion molecules and chemokine receptors, and downregulates the production of proinflammatory cytokines and other molecules.168

 Keratinocytes express MC-Rs and POMC and release α-MSH. α-MSH production by keratinocytes is increased by UV light and proinflammatory stimuli such as lipopolysaccharide (LPS) and IL-1. There is also evidence that the melanocortin system is involved in keratinocyte proliferation and differentiation. Since α-MSH has a variety of immunomodulatory and anti-inflammatory activities by downregulating the production of proinflammatory cytokines such as IL-1, IL-6, and TNF-α in several cell types and downregulating the expression of adhesion molecules on endothelial cells as well as inhibiting NF-kB activation. Very recent data indicate that the anti-inflammatory effects by H-bonds of α-MSH may be mediated via interaction of α-MSH with IL-1R1. Accordingly, an α-MSH related tripeptide, KdPT, was found to bind to IL-1R1 and one hydrophobic bond. α-MSH also induces IL-10 expression by human keratinocytes. These findings, together with the observation that systemic application of α-MSH blocks contact hypersensitivity (CHS) in mice and induces antigen-specific tolerance, indicate that α-MSH released in the skin after UV-irradiation may be one of the mediators responsible for UV-mediated immunosuppression.49,169 The role of α-MSH as mediator of inflammation is further strengthened by finding that α-MSH blocks cytokine and mediator release by mast cells and basophils.49 Moreover, α-MSH appears to be involved in the regulation of an immune response, since upon treatment with α-MSH, dendritic cells remain in an immature stage and induce regulatory T cells.170 There is recent evidence that α-MSH plays a crucial role in the development of cytotoxic CD8+ T cells and thereby contributes to major histocompatibility complex (MHC) class I restricted cytotoxicity.171

 There is increasing evidence that α-MSH also modulates dermal fibroblast function since they have been shown to express MC1-R. Furthermore, a role of α-MSH as regulator of the extracellular matrix of the skin is supported by studies demonstrating an effect of α-MSH and collagen synthesis induced by TGF-β1, a key profibrotic cytokine implicated in the pathogenesis of fibrotic disorders including systemic sclerosis.172 The activity of α-MSH and its regulation of the collagen metabolism in conjunction with its anti-inflammatory activities could be of special value for the future therapy of fibrotic disorders.173

 Several lines of evidence indicate that melanocortins in the skin may function as part of the innate defense that ultimately protects the skin against environmental stress, infectious agents, and genotoxic stimuli. Accordingly, MCs induce melanogenesis to prevent the generation of skin cancer. α-MSH also was found to exhibit antimicrobial activity.174 Recently, it has been reported that α-MSH is able to protect melanocytes as well as keratinocytes from the most ubiquitous environmental stressor UV light via exerting an antiapoptotic activity.175 This may also explain the increased incidence of melanomas in patients with loss of function of MC1-R.49,176 Therefore, in the epidermis α-MSH may maintain the crucial pigment producing function of melanocytes and via reducing UVB-induced DNA damage, it may enhance genomic stability of both melanocytes and keratinocytes.

 Anti-inflammatory effects of α-MSH have been confirmed in vivo using various animal models including irritant or allergic contact dermatitis, cutaneous vasculitis, asthma, inflammatory bowel disease, rheumatoid arthritis, and ocular and brain inflammation. Most of the anti-inflammatory activities of α-MSH can be attributed to its C-terminal tripeptide KPV, K(D)PT.177 Therapeutic potential has been also suggested in acne vulgaris178 or, for example, scleroderma.172

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Corticotropin-Releasing Hormone

 CRH expression is highly responsive to common stressors such as ultraviolet radiation or immune cytokines.29,30,179,180 CRH acts also as a proinflammatory mediator, induces skin mast cell degranulation, thereby increasing vascular permeability.181 In contrast, administration of CRH has anti-inflammatory effects in thermally injured skin, and together with urocortin, reportedly inhibited proliferation of keratinocytes or induced keratinocyte differentiation.182 The human skin expresses high levels of CRH receptors. Of note, the CRH receptor CRH-R1α was expressed in all major cellular populations of the epidermis, dermis, as well as subcutis. The CRH-R2 receptor was detected mainly in hair follicles, sebaceous and eccrine glands as well as blood vessels.183 By acting on many skin cells (e.g., keratinocytes, sebaceous glands) and immune cells (e.g., mast cells), targeting CRH receptors may be beneficial for the treatment of various skin diseases including acne or urticaria.181,184–186

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Neuropeptide-Degrading Enzymes

 Recent studies indicate that a variety of peptidases play an important role in the control of cutaneous neurogenic inflammation. For example, the metallo-endopeptidases ACE and ECE are capable of degrading the tachykinin SP, bradykinin, and angiotensin, whereas NEP additionally cleaves NKA, NKB, VIP, (PACAP-27), ANP, SST-14, and endothelins.187 PACAP-38 is not degraded by NEP.188 Recently, cell surface-located serine dipeptidyl peptidase IV was found to inactivate PACAP-38 in vivo and in vitro.189 Thus, endopeptidases tightly regulate the capability of neuropeptides to activate their cognitive receptors on the cell membrane.

 ACE is predominantly found on the luminal side of vascular endothelium, which limits its range of actions predominantly to vascular responses (vasodilatation, plasma extravasation, leukocyte-endothelium adhesion).190 In the skin, both NEP and ACE have been identified in vascular endothelial cells,191 skin fibroblasts,192 and keratinocytes.193,194

 Conclusive evidence for the role of ACE and NEP in modulating a number of biological processes derives from studies of mice in which the gene for ACE or NEP has been deleted by homologous recombination. Deletion of NEP in NEP(−/−) mice renders them sensitive to endotoxic shock.195 In the skin, NEP(−/−) mice showed an increased constitutive plasma extravasation from postcapillary venules in several tissues including skin. Moreover, in a model of experimentally induced contact dermatitis of the ear, NEP(−/−) mice demonstrated a significant increase of plasma extravasation and cutaneous inflammation that peaked after 6 hours.191,196 This leakage was attenuated by injection of recombinant NEP, or antagonists against NK1R and BK2-R, respectively. Thus, inhibition or genetic deletion of NEP impairs the degradation of the proinflammatory mediator bradykinin and SP that results in an increased vasodilatation and plasma extravasation mediated by NK1R and BK2-R.195

 NK1R and NEP are often coexpressed by the same target cell. Despite the approximately 10,000-fold lower affinity of SP to NEP compared to that to NK1R, NEP can efficiently inhibit NK1R signaling, if expressed at high concentrations and in the vicinity of NK1R at the cell surface.197 Once neuropeptides are activated and released on target cells, peptidases may be important for degrading these molecules in the extracellular space.

 Recently, splice variants of NEP and ECE have been characterized. Interestingly, these variants are partially localized intracellularly, inside the endo- and exocytotic pathways of these cells. This observation suggests that both transmembrane as well as intracellular peptidase activity may play a major regulatory function in receptor resensitization.198,199

 Although the level of endopeptidase expression is important because of its activity on skin cells, its regulation is not well characterized. So far, NEP activity is known to increase after stimulation with proinflammatory cytokines,200 by agents that increase the intracellular cAMP level201 and glucocorticoids that also downregulate NK1R expression.202,203 Moreover, both NEP and ACE expression is upregulated during wound healing.204

 A new peptidase regulating neuropeptide receptor resensitization and intracellular cell signaling is ECE-1 (ECE-1). ECE-1 can be found on the cell surface where it activates endothelin. However, when the neuropeptide/neuropeptide receptor complex for SP, CGRP or somatostatin (SST) is endocytosed, the neuropeptides become sequestered within the endosome, and the receptor becomes capable to recycle to the cell surface and resensitize. Accordingly, β-arrestins can return to the cytosol and205–207 mediate mitogen-activated protein (MAP) kinase signaling or cell apoptosis. Thus, peptidases are crucial regulators of neuropeptide receptor resensitization, cell signaling, and apoptosis.205,207–209

 In summary, these findings imply that upregulation of endopeptidases is an important mechanism of limiting proinflammatory effects of degradable neuropeptides by reducing their pericellular concentrations close to the receptor. Thus, downregulation of neuropeptide degrading enzymes, on the other hand, may result in uncontrolled function of neuropeptides and disease.

 (See also Chapter 36)

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Bradykinin and Kinins

 Bradykinin plays an important role in inflammation, inflammatory pain and angioedema. Topical as well as systemic application has demonstrated bradykinin to be a transducer of pain but probably not pruritus (although under debate). This is most probably mediated via activation of bradykinin-2 (B2) receptors.

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Histamine and Serotonin

 Imidazolethylamine, better known as histamine, is synthesized from the amino acid l-histidine through oxidative decarboxylation by histidine decarboxylase (HDC) and occurs in tissues throughout the body. The precise function of histamine is dependent on its tissue localization: for example, in the nervous system, it operates as a neurotransmitter and in the immune system, gut, and skin, it serves as a signaling molecule. Since the first description of histamine more than a century ago, many important implications on human health have been assigned to this molecule. This importance may derive mainly from the central role histamine plays in inflammatory processes. In early cutaneous inflammation some researchers consider histamine to be the “quintessential mediator.” In fact, histamine has been described to trigger the characteristic triad of inflammation—redness (hypersemia), wheal (edema), flare (vasodilatation)—along with induction of marked pruritus in the skin. The sources of cutaneous histamine are reported to be mast cells and keratinocytes, which release the molecule upon stimulation.

 Histamine exerts its action through binding to distinct metabotropic histamine receptor subtypes. To date, four histamine receptor subtypes are known and cloned. All four belong to the rhodopsin-like family of G protein-coupled receptors (GPCR). Also several isoforms exist for each receptor subtype which emerge from different transcriptional and posttranscriptional processing, Remarkably, the histamine receptors display a high degree of functional heterogeneity as well as discriminable expression patterns and a distinct utilization of intracellular signaling mechanisms. Differences in the functionality of histamine receptor splice variants are not reported so far. In the skin, the expression of two of the histamine receptors, H1R and H2R, has been detected but most histamine-mediated dermatological effects are so far attributed to the classical H1R.

 Histamine also regulates T cell function, immune cell trafficking, and adaptive immune defense during chronic inflammation.210,211 In these cells, histamine can induce various intracellular signaling pathways including protein kinase C, phospholipase A2, or NF-κB, for example. H1R and H2R receptor activation leads to reciprocal activation of T cells with respect to Th1/Th2 differentiation, and specific cytokine regulation. The impact of H4R expression on numerous immune and inflammatory cells is still poorly understood. Currently, antagonists, agonists, or inverse agonists targeting H1R, H3R, or H4R are being developed or are employed in clinical trials for the treatment of allergic reactions, inflammation and pruritus.9,212

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TRP Ion Channels and Activators

 The somatosensory effects of natural products such as capsaicin, mustard oil, camphor, garlic or menthol are well known. Moreover, a receptor for sensing temperature changes has been anticipated for a long time. The identification of transient receptor potential vanilloid-1 (TRPV1) in primary sensory neurons as the receptor for vanilloids, capsaicin, heat, and pH changes has led to a novel understanding in skin biology and disease.

 Endovanilloids interact with TRPV1, an ion channel that belongs to the superfamily of transient receptor potential (TRP) channels. To date six groups of molecules complete this superfamily: (1) the canonical (TRPC), (2) the melastatin (TRPM), (3) the polycystin (TRPP), (4) the ankyrin transmembrane protein 1 (TRPA), (5) the mucolipin (TRPML), and (6) the vanilloid (TRPV) subfamilies. All members of this superfamily act as nonselective calcium-permeable sensory transduction channels.213 Endovanilloids constitute a group of itch mediators to which heterogeneous agents such as eicosanoids, histamine, bradykinin, ATP, and various neurotrophins (NTs)214–217 belong, where all agents share endovanilloid functions.218 These agents either directly and/or indirectly activate/sensitize vanilloid receptor-1 (TRPV1).28,215,219

 TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8 are involved in nociception, and probably other functions. TRPV6 may be involved in keratinocyte differentiation. Agonists or antagonists of these channels are currently under development for the treatment of inflammation, pain, pruritus, or cancer.

 Originally, TRPV1 was found to be expressed by nociceptive sensory neurons28 as an integrator of different pain-inducing stimuli. Its most well known activator is capsaicin, the pungent ingredient of hot chili peppers. Administration of this compound excites219 but then desensitize sensory afferents via TRPV1 activation, a mechanism that is utilized to alleviate pain and itch in numerous skin diseases.219–222 More precisely, vanilloid administration leads to a depletion of neuropeptides in the C-fibers, which disrupts the communication between mast cells and skin sensory neurons.221–223 Interestingly, also the calcineurin inhibitors tacrolimus224 and pimecrolimus225 bind to TRPV1 suggesting a mode of action for these clinically important compounds.

 Only recently, functional TRPV1 channels were detected on numerous nonneuronal cell types,226–228 including human epidermal and hair follicle keratinocytes, dermal mast cells, and dendritic cells.173,229–231 TRPV1 activation resulted in the release of pruritogenic cytokine mediators from several of these nonneuronal cells. In keratinocytes, TRPV1 was furthermore reported to mediate proliferation, differentiation, and apoptosis, respectively,232,233 but recent results, utilizing a functional approach with both systemic and local resiniferatoxin (RTX) treatment, question a functional expression of TRPV1 in primary human keratinocyte.234 It will be a subject of further detailed research to show whether endovanilloid itch mediators, besides acting on their cognate receptors, activate/sensitize TRPV1 expressed on itch-mediating sensory neurons only or also address TRPV1 expressed on other skin cells. In other words, topically applied capsaicin may not only desensitize TRPV1-mediated signaling in neuronal cells but may also provoke TRPVI-mediated signaling in the many other skin cells to counteract a pruritogenic outcome.

 Next to TRPV1, itching sensitization might also be related to the activation of other TRPs expressed in the skin, sensory fibers, and keratinocytes including TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8.235 In fact, an important role for TRPV3 in pruritus has been shown recently. Asakawa and colleagues discovered an amino-acid substitution (G573S) in TRPV3 that led to an increase in ion channel activity in keratinocytes that caused a spontaneous pruritic dermatitis in mice.236 TRPA1 is also expressed by keratinocytes, and may play an important role in vasoregulation.237,238

 It is well known that the intradermal pH is decreased during skin inflammation. Protons can activate the TRPV1 receptor (“capsaicin receptor”), but also the acid-sensing ion channel 3 (ASIC-3; DRASIC) (Dorsal root ganglia specific), both of which are expressed in the skin.

 In human skin, TRPV1, TRPV2, and TRPM8 are expressed on primary sensory neurons, and TRPV2 and TRPM8 immunoreactive nerve fibers can be found at the dermal–epidermal border, around blood vessels and hair follicles, although less abundant than TRPV1. The TRPV2 and TRPM8 colocalized with CGRP and SP, thus peptidergic C-fibers. These fibers were reduced in number in patients with Norrbottnian congenital insensitivity to pain, an autosomal disease selectively affecting the development of C-fiber and A-δfiber primary afferents.239

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Cannabinoids and Receptors

 The role of CB in the regulation of peripheral neuronal effects is only partly understood and has been extensively reviewed recently.1,240–242 Cannabinoids provoke antinociceptive and antihyperalgesic effects in rodents and humans.243 CB are also expressed by various immune cells.244,245 CB inhibit the production of cytokines during innate and adaptive immune responses246–248 (eTable 102-0.1). Cannabinoids are also involved in T cell regulation.249,250 Functional studies further indicate a role of macrophage-derived CB2 in the progression of autoimmune diseases such as multiple sclerosis,251,252 or HIV.253 Cannabinoid agonists attract human eosinophils,254 B cells,255 and dendritic cells.256 They also downregulate the release of chemokines such as CXCL8 and reduce cutaneous edema.257

 In the skin, expression of CB1 and CB2 was detected in neurons, keratinocytes, cutaneous mast cells, and macrophages by immunofluorescence.258 Recently, CB were detected in human epidermal keratinocytes which also express the CB1R suggesting a role of CB in epidermal differentiation and skin development.259 CB2Rs may be involved in the regulation of pain and pruritus in cutaneous sensory nerves.149,218,260–263 Given its wide distribution of CB receptors both on skin and immune cells, antagonists of CB receptors may be beneficial targets for the treatment of skin diseases.264,265

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Adenosine and Adenosine Phosphates

 Upon injury (e.g., microbes, wounding, UV radiation) or pain induction, purines and pyrimidines are inducible mediators generated by various cells of many organs. The adenosine (P1) receptor family consists of four subtypes, while the P2 (activated by ATP, ADP and UTP) receptor family can be divided into P2X ionotropic receptors (seven subtypes) and P2Y metabotropic G protein-coupled receptors (eight subtypes). Purinoceptors are expressed both by neuronal and nonneuronal cells including keratinocytes, endothelial cells, and leukocytes. Purinergic receptors are involved in innate immunity, pain, exocrine and endocrine secretion, platelet aggregation, and vasoregulation. Trophic functions include cell turnover, proliferation, differentiation, and apoptosis in various skin cells, neural regeneration, wound healing, and cancer. ATP induces Ca-mobilization from intracellular stores in keratinocytes and thereby proliferation in vitro266 and stimulates cytokine (IL-6) as well as chemokine (CXCL1–3) release from these cells, probably via STAT-3 and ATF3 activation.267,268

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Cytokines and Chemokines from a Neuronal Perspective

Cytokines are capable of inducing pruritus, and, conversely, cytokine inhibitors have been demonstrated to reduce neurogenic inflammation, pain, and pruritus. Thus, cytokines and chemokines may communicate with sensory nerves via high-affinity receptors269–274 (see eFig. 102-0.1 and Table 102-1).

“Neurophilic” cytokines include IL-1, IL-6, IL-8, and IL-31.48,52 Of note, transgenic mice overexpressing IL-31 released by T cells and macrophages developed a chronic inflammatory skin disease characterized by a T-cell infiltrate and pruritus, similar to atopic dermatitis in humans. IL-31 activates the IL-31 receptor (IL-31R), a heterodimeric receptor composed of the IL-31R A subunit and the oncostatin M receptor subunit. Whether IL-31 exerts its pruritic effects via direct activation of IL-31R on sensory nerves or indirectly (e.g., via keratinocytes) is currently unknown. The finding that keratinocytes express IL-31R suggests that IL-31 may induce pruritus through the induction of a yet unknown keratinocyte-derived mediator that subsequently activates unmyelinated C fibers in the skin. Therefore, one may speculate that IL-31 is upregulated in pruritic forms of cutaneous inflammation.275,276 These findings were confirmed in mice: the expression of cutaneous IL-31 messenger RNA was significantly higher in NC/Nga mice with scratching behavior than in NC/Nga mice without scratching behavior.277 Therefore, IL-31 may participate in causing an itch sensation and promoting scratching behavior.278,279 In addition, IL-31 may be also a link in the communication between eosinophils and keratinocytes in pruritic inflammatory skin diseases.280–282 Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. A gene mutation has been recently described in PCA, a pruritic skin disorder associated with amyloid deposits in the superficial dermis.283 Together, IL-31 may serve as a link between the immune and neural systems by regulating inflammation as well as itch. For this reason, IL-31 and the IL-31R are promising targets for the treatment of inflammatory and itchy dermatoses such as atopic dermatitis, urticaria, and other genetically associated pruritic diseases. Various antagonists such as the OSMR-L-GPL fusion protein are currently under investigation.284

A number of human clinical diseases or symptoms, appear to have a significant neurogenic component, including atopic dermatitis, prurigo, pruritus-associated diseases, psoriasis, rosacea, urticaria, herpes zoster, or inflammatory arthritis (see eTable 102-0.1).1 The peripheral nervous system also modulates inflammatory responses or symptoms in other organs, such as eye inflammation, asthma, inflammatory bowel syndrome, and transmits pain. Moreover, neuronal mediators play a role during wound healing by regulating growth, proliferation, and angiogenesis.

The ability of neuropeptides to activate human mast cells and induce urticaria has been appreciated for a number of years.285 For example, chronic idiopathic urticaria and, to a lesser extent, pressure urticaria showed enhanced SP- and CGRP-induced wheal-and-flare reactions (see Fig. 102-1). Certain transient receptor potential ion channels are expressed by sensory nerves as well as by mast cells that can be activated by trigger factors of urticaria like heat, cold, pressure, or food ingredients.

A neurogenic component in the pathophysiology of psoriasis is suggested based on clinical observation (e.g., stress induction) and is supported by experimental studies.286–289 Data suggest a role for NGF as a mediator of inflammatory responses in psoriasis, although its significance remains to be established.290

In acute as well as lichenified lesions of atopic dermatitis, increased staining of cutaneous nerves or concentrations of neuropeptides has been observed.80,139,291–297 Also, characteristics of the triple response (erythema, wheal, flare) of neurogenic inflammation as well as pruritus have been observed after injection of neuropeptides into human skin.298,299 The lesions of patients with atopic dermatitis show enhanced concentrations of mast cell tryptase, a ligand for the proteinase-activated receptor-2 (PAR-2), which is upregulated in atopic dermatitis and mediates pruritus, inflammation, and upregulation of intercellular cell adhesion molecule 1 or nuclear factor κB.300–303 A role for proopiomelanocortin peptides in the pathogenesis of atopic dermatitis is supported by the in vitro observation that α-MSH modulates immunoglobulin E production and the finding of increased levels of proopiomelanocortin peptides in the skin of patients with atopic dermatitis.304,305 Some studies also suggest that NTs such as NGF or NT-3 may participate in the pathophysiology of atopic dermatitis (Table 102-2).306

Neuropeptides such as CGRP, PACAP, or α-MSH, are obviously involved in the regulation of epidermal antigen presentation.307–310 Also, pretreatment of the skin with capsaicin enhances contact hypersensitivity (CHS) at the site of treatment. It has been suggested that capsaicin-sensitive neurons modulate this reaction via the release of neuropeptides.114,311 Studies also indicate that SP agonists can prevent impaired CHS and tolerance after UVB irradiation.191 CGRP significantly inhibited antigen presentation to antigen-specific T cells.114,312 The effect of CGRP on murine LCs is probably mediated by a specific CGRP receptor, which leads to intracellular increase in cyclic adenosine monophosphate.113 Accordingly, IL-10 can be upregulated by CGRP.313 α-MSH is one of the most powerful neurohormones in terms of its ability to modify CHS reactions.314–316 PACAP is also able to inhibit CHS reactions.310

The skin nervous system also plays a crucial role during wound healing and impaired wound healing processes. Released neuropeptides participate in inflammation, cell proliferation, cytokine, and growth factor production, and neovascularization.317,318 Of note, delayed wound healing occurred in animal models after surgical resection of cutaneous nerves.319–323 For instance, decreased concentrations of SP, SST, and CGRP were observed in wounds in rats324; elevated levels can be observed in other wound models.321,324 CGRP promotes proliferation and migration of human keratinocytes325–327 and stimulates proliferation of human dermal endothelial cells.328 VIP has both inhibitory and stimulatory effects on the proliferation of keratinocytes.325,326,329 Angiotensin II appears to influence tissue repair via activation of the angiotensin I receptor in fibroblasts, which leads to collagen remodeling, collagen gel contraction, and upregulation of collagen-binding integrins in vitro.330 NGF induces human skin and lung fibroblast migration but not proliferation.331 In a mouse model, it could be observed that NGF accelerated the rate of wound healing.332 These findings have encouraged successful treatment of leg ulcers in humans with topical NGF.333,334 Parathyroid hormone-related protein expression is temporarily upregulated in migratory keratinocytes, myofibroblasts, and infiltrating macrophages in guinea pig skin, although topical application of a parathyroid hormone-related protein agonist did not change the healing rate or morphology in these wounds.335,336

NEP expression appears to be both increased and redistributed in the wound environment during wound healing, which indicates a role for neuropeptide-degrading enzymes in this process.337 In normal skin, NEP immunoreactivity was restricted to the basal layer, whereas during wound healing, NEP was also detected in the suprabasal layer of human skin. Future studies using transgenic and knockout animals, in which certain components of the neurologic system are overexpressed or deleted by homologous recombination, may make it possible to examine the role of the cutaneous nervous system in normal and delayed wound healing.338

Pruritus is one of the most frequent symptoms of skin diseases and derives from stimulation of sensory nerve endings, spinal cord modulation, or dysfunction of certain areas in the CNS (see eTable 102-0.1).48,65,222,339 Polymodal C fibers, stimulated by chemicals or heat, transmit signals to the spinal cord and CNS, which results in itching. Accordingly, both the peripheral cutaneous system and the CNS coordinate the sensation of itch, which leads to the autonomic reflex of scratching. Histamine is the best-studied, albeit definitely not the only, mediator of pruritus. New histamine receptors (e.g., histamine receptor-3, histamine receptor-4) have now been cloned; their role in human itch is poorly understood.212 Another important mediator of pruritus in patients with atopic dermatitis may be IL-31 (see Table 102-1, eFig. 102-0.1).275,279,340,341 In notalgia paresthetica, a neuropathy characterized by pruritus, pain, and hyperalgesia, immunostaining for several neuropeptides revealed that affected areas had a significant increase in intradermal nerve fibers as well as epidermal dendritic cells, which suggests that sensory nerve fibers are involved in the pathogenesis of this disease. Agents such as capsaicin that deplete neuropeptides from sensory neurons have been shown to have a therapeutic effect in diseases associated with pruritus and pain. Other neuromediators such as opioids seem to be involved in the pathophysiology of cholestatic pruritus.342,343 Cholestatic pruritus can be significantly reduced by application of an antagonist to 5-hydroxytryptamine.344 Like opioids, endogenous CB appear to be implicated in itching.48,65,261,345 Under inflammatory conditions,346 CB are capable of activating and sensitizing the TRPV1 receptor.347,348 Cannabinoid receptors also induce release of analgesic β-endorphin from murine keratinocytes.149 Aprepitant, a selective NK1R antagonist, which has been recently demonstrated to be beneficial for the treatment of pruritus and prurigo,75 may also be beneficial for the treatment of other pruritic skin diseases.

In many ways, the nervous system modulates (and eventually “manipulates”) the function of the skin, which under physiological conditions leads to control of skin homeostasis. However, under pathophysiological conditions, neuromediators can either aggravate (proinflammatory) or ameliorate (anti-inflammatory) disease development. The bidirectional interaction of the skin with the peripheral nervous system as well as the CNS plays a crucial role in skin homeostasis and disease states, as seen for inflammation, pain, or pruritus. Recent discoveries have increased our knowledge about the molecular mechanisms regulating the function of neuromediators, their receptors, and controlling enzymes. The development of modern techniques including proteomics, genomics, metabolics, and molecular imaging of neuronal structures offer exciting insights into the complex network between skin, nerves, and immune system during inflammation, tumorigenesis, pruritus, or chronic pain. Various applications like TRPV1 channel agonists/antagonists or neuropeptide receptor antagonists are currently in clinical or preclinical trials for the treatment of various skin diseases including atopic dermatitis, rosacea, viral infection, pruritus, or pain. Using novel technical approaches and understanding new pathways of neuro-immuno-endocrine communication, it will be possible to learn how neuromedicine can contribute to treat skin diseases and symptoms such as inflammation, cancer, pigmentation disorders, allergic reactions, endocrine disregulation, painful skin diseases, or pruritic diseases.