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Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ DIRK ROOSTERMAN, TOBIAS GOERGE, STEFAN W. SCHNEIDER, NIGEL W. BUNNETT, AND MARTIN STEINHOFF Department of Dermatology, IZKF Mu ̈nster, and Boltzmann Institute for Cell and Immunobiology of the Skin, University of Mu ̈nster, Mu ̈nster, Germany; and Departments of Surgery and Physiology, University of California, San Francisco, California I. Introduction 1310 II. Anatomy and Physiology of the Cutaneous Nervous System 1311 A. Neuroanatomy and neurophysiology of cutaneous nerves 1311 B. The “Skin-Sensory PNS-CNS connection” exemplified by itching 1312 C. Neuroanatomy and neurophysiology of autonomic nerves 1313 III. Biological Activities of the Cutaneous Sensory Nervous System 1318 A. Towards a modern concept of neurogenic inflammation 1318 B. Cutaneous neuropeptides and neuropeptide receptor biology 1319 IV. Acetylcholine, Catecholamines, and Their Receptors 1333 A. ACh and receptors 1333 B. Catecholamines and receptors 1335 C. Adrenergic receptors 1336 V. Neurotrophins and Neurotrophin Receptors 1336 A. Neurotrophins in the skin 1336 B. NGF and NT receptors 1336 C. NGF and cutaneous inflammation 1337 VI. Role of Capsaicin and Transient Receptor Potential Ion Channels in the Skin 1338 A. TRPV1 1338 B. TRPV2 1339 C. TRPV3 1339 D. TRPV4 1340 E. TRPM8 1340 F. TRPA1 1340 VII. Role of Proteinase-Activated Receptors in Cutaneous Neurogenic Inflammation and Pruritus 1341 VIII. Cytokines and Chemokines as Ligands for Skin Sensory Nerves 1341 IX. Molecular Mechanisms Regulating Neurogenic Inflammation 1342 A. Synthesis, posttranslational processing, and secretion of neuropeptides 1343 B. Coexistence of neurotransmitters 1343 C. Mechanisms regulating neuropeptide receptor function 1343 X. Role of the Nervous System in Skin Pathophysiology 1347 A. Urticaria 1347 B. Psoriasis 1348 C. Atopic dermatitis 1348 D. Immediate and delayed-type hypersensitivity 1349 E. Wound healing 1351 F. Pruritus 1352 XI. Therapeutic Approaches for the Treatment of Cutaneous Diseases With a Neuroinflammatory Component 1354 XII. Conclusions and Future Directions 1355 Roosterman, Dirk, Tobias Goerge, Stefan W. Schneider, Nigel W. Bunnett, and Martin Steinhoff. Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ. Physiol Rev 86: 1309–1379, 2006; doi:10.1152/physrev.00026.2005.—This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous Physiol Rev 86: 1309–1379, 2006; doi:10.1152/physrev.00026.2005. www.prv.org 0031-9333/06 $18.00 Copyright © 2006 the American Physiological Society 1309 by 97.96.42.6 on October 28, 2017 http://physrev.physiology.org/ Downloaded from
nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases. I. INTRODUCTION Substantial evidence has accumulated that the cuta- neous peripheral nervous system (PNS) plays a pivotal role in skin homeostasis and disease. First, the innervated skin is a crucial barrier protecting the body from danger from the “external environment.” Cutaneous nerves also respond to stimuli from the circulation and to emotions (“internal trigger factors”). Moreover, the central nervous system (CNS) is directly (via efferent nerves or CNS- derived mediators) or indirectly (via the adrenal glands or immune cells) connected to skin function (Fig. 1). Sensory as well as autonomic (sympathetic) nerves influence a variety of physiological (embryogenesis, vasocontraction, vasodilatation, body temperature, bar- rier function, secretion, growth, differentiation, cell nu- trition, nerve growth) and pathophysiological (inflam- mation, immune defense, apoptosis, proliferation, wound healing) functions within the skin. In unstimu- lated nerves, neuromediators are barely detectable within the skin tissues. Upon direct stimulation by physical stimuli (thermal, ultraviolet light, mechanical, electrical), chemical, or indirect stimuli such as aller- gens, haptens, microbiological agents, trauma, or in- flammation, a significant increase of regulatory neu- ropeptides, neurotrophins, neurotransmitters, or oxy- gen products (e.g., nitric oxide) can be detected in vitro and in vivo. Thus mediators derived from sensory or FIG. 1. The skin as a neuroimmunoendocrine organ. The skin is associated with the peripheral sensory nervous system (PNS), the autonomous nervous system (ANS), and the central nervous system (CNS). 1) Various stressors activate the hypothalamus/hypophysisis within the CNS which results in the 2) release of neuromediators such as corticotropin-releasing hormone (CRH), melanocyte stim- ulating hormone (MSH), pituitary adenylate cyclase acti- vating polypeptide (PACAP), or MIF, for example. They may stimulate either the release of 3) norepinephrine and cortisol from the adrenal glands or 4) directly stimulate leukocytes in the blood system via CRH, MC, or PAC receptors, thereby modulating immune responses during inflammation and immunity. Norepinephrine and cortisol effect several immune cells including lymphocytes, gran- ulocytes, and macrophages. 5) Immune cells release cyto- kines, chemokines, and neuropeptides that modulate in- flammatory responses in the skin. 6) Upon stimulation, sensory nerves release neuromediators (Fig. 2, Table 2) that modulate cutaneous inflammation, pain, and pruritus. Skin inflammation affects activation of immune cells via cytokines, chemokines, prostaglandins, leukotrienes, ni- tric oxide, and MSH (see Table 2 for details), which may have a proinflammatory [e.g., substance P (SP)] or anti- inflammtory effect [e.g., calcitonin gene-related peptide (CGRP), PACAP] by upregulating or downregulating in- flammatory mediators such as cytokines or tumor necrosis factor (TNF)-, for example. 7) Autonomous nerves, in the skin mainly sympathetic cholinergic and rarely parasym- pathetic cholinergic nerves innervate several cells in the skin, thereby maintaining skin homeostasis and regulating inflammation as well as host defense (see Fig. 4 for details). 1310 ROOSTERMAN ET AL. Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org by 97.96.42.6 on October 28, 2017 http://physrev.physiology.org/ Downloaded from
autonomic nerves may play an important regulatory role in the skin under many physiological and patho- physiological conditions. Beside the periphery, how- ever, a subtle complex communication network exists between the spinal cord, the CNS, and the immunoen- docrine system. Figure 1 summarizes the mediators involved in regulating the neuroimmunoendocrine net- work. II. ANATOMY AND PHYSIOLOGY OF THE CUTANEOUS NERVOUS SYSTEM A. Neuroanatomy and Neurophysiology of Cutaneous Nerves The anatomy and classification of cutaneous sensory nerves has been extensively reviewed by Winkelmann (940). According to the classification of Halata, sensory nerves are based on two groups: the epidermal and the dermal skin-nerve organs. Both can be subdivided: the epidermal skin-nerve organs consist of “free” nerve end- ings or hederiform nerve organs (e.g., Merkel cells). The term free terminal nerve ending refers to a slight axon expansion that still contains perineural cells including cytoplasm of Schwann cells and multiple cell organelles (459, 881). In the dermal part, free sensory nerve endings, the hair nervous network (Pinkus discs), and the encap- sulated endings [Ruffini, Meissner, Krause, Vater-Pacini (vibration), mucocutaneous end organ] have to be differ- entiated (Table 1). Neurophysiological studies have led to a more advanced functional classification of sensory nerves based on the type of cutaneous mechanoreceptor responses (Table 1). Sensory nerves can be subdivided into four groups: A fibers (12–22 mm) are highly myelinated, show a fast conduction velocity (70–120 m/s), and are associated with muscular spindles and tendon organs. A fibers are mod- erately myelinated (6–12 m) and capture touch recep- tors. A fibers constitute a thin myelin sheath (1–5 m), an intermediate conduction velocity (4–30 m/s), and are generally polymodal. The slow-conducting C fibers (0.5–2 m/s) are unmyelinated and small (0.2–1.5 m). A fibers constitute 80% of primary sensory nerves sprouting from dorsal root ganglia, whereas C fibers make up 20% of the primary afferents (14, 470). Moreover, the activa- tion threshold of A fibers is higher than that of C fibers. In human peripheral nerves, 45% of the cutaneous afferent nerves belong to a subtype of sensory nerves that are mechano-heat responsive C fibers (C-mh) (729). However, only 13% of these nerves were found to be only mechanosensitive (C-m), 6% were heat sensitive (C-h), 24% were neither heat nor mechanoresponsive (C-mh), and 12% were of sympathetic origin; 58% of C-mh responded to mustard oil, and 30% of C-m or C-mh did so (729). Both C and A fibers respond to a variable range of stimuli such as physical (trauma, heat, cold, osmotic changes, distension or mechanical stimulation, ultraviolet light) as well as chemical (toxic agents, allergens, pro- teases, microbes) agents (reviewed in Ref. 811). However, although A fibers can also respond to chemical stimuli, their role in neurogenic inflammation and pruritus is still poorly understood. On the molecular level, specific receptor distribution seems to be important for the various functions of sen- sory nerve subtypes. For example, mechanoreceptors ex- clusively express the T-type calcium channel Ca(v)3.2 in the dorsal root ganglion (DRG) of D-hair receptors. Phar- macological blockade indicates that this receptor is im- portant for normal D-hair receptor excitability including mechanosensitivity (758). However, different mecha- nisms seem to underlie mechanosensory function in var- ious tissues. In the gut and skin, for example, the de- TABLE 1. The neurophysiological characteristics of sensory nerves in the skin Category Stimulus Physiological Type Anatomy Type Nerve Type Sensation Low-threshold mechanoreceptors Displacement Type I Hair disc A ? SA I Merkel cell complex A Pressure Type II ? Ruffini ending A ? SA II A ? Displacement velocity GI hair Hair palisade A Hair movement RA field receptor Meissner corpuscle A Tapping D hair Hair follicle A ? C mechanoreceptor Nerve network? C ? Vibrations Pacinian corpuscle Pacinian corpuscle A Buzzing Nerve network Thermoreceptors Cooling Cold receptor Nerve network C, A Cold Warming Warm receptor Nerve network C Warm Nocireceptors Noxious deformation Myelinated A Sharp pain Noxious heat, chemicals Unmyelinated C Dull pain, sharp pain, burning pruritus SKIN NEUROBIOLOGY 1311 Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org by 97.96.42.6 on October 28, 2017 http://physrev.physiology.org/ Downloaded from
generin/epithelial Na channel (DEG/ENaC) ion channel ASIC1 influences visceral but not skin mechanosensation (612). Inflammation and trauma induce the activation and/or sensitization of nociceptors (769, 770). During chronic inflammation, pain, or pruritus, prolonged noci- ceptor activation may occur, thereby increasing the sen- sitivity of nociceptors which may lead to the perpetuation of neuronal stimulation and thus progression. In the skin, cutaneous nerve fibers are principally sensory, with an additional complement of autonomic nerve fibers (114, 563). In contrast to sensory nerves, autonomic nerves never innervate the epidermis in mam- mals. Sensory nerves innervate the epidermis and dermis as well as the subcutaneous fatty tissue as a three-dimen- sional network (425, 881, 951). Most of the nerve fibers are found in the mid-dermis and the papillary dermis. The epidermis, blood vessels, and skin appendages such as hair follicles, sebaceous glands, sweat glands, and apo- crine glands are innervated by several subtypes of sensory nerves (622, 811). Regional-specific differences can be observed with respect to the mucocutaneous border, the glabrous skin, and hairy skin (940). With the use of electron microscopy (336), confocal laser scan microscopy (671), and immu- nohistochemistry (809), it is possible to demonstrate that the epidermis is also innervated by a three-dimensional network of unmyelinated C fibers with free-branching endings that arise in the dermis and their basement mem- brane apposed to epidermal cells such as keratinocytes, melanocytes, Langerhans cells, and Merkel cells, respec- tively. Increased epidermal innervation has been de- scribed in skin lesions of various inflammatory skin dis- eases (379, 383, 633, 640, 761, 809), wound repair (234), skin cancer (232, 447, 552, 567, 765), epithelial hyperplasia (702), after exposure to ultraviolet (UV) light, or during psoralen UVA therapy (525, 785). B. The “Skin-Sensory PNS-CNS Connection” Exemplified by Itching The skin is innervated by afferent somatic nerves with fine unmyelinated (C) or myelinated (A) primary afferent nerve fibers transmitting sensory stimuli (temper- ature changes, chemicals, inflammatory mediators, pH changes) via dorsal root ganglia and the spinal cord to specific areas of the CNS, resulting in the perception of pain, burning, burning pain, or itching (Table 1, Fig. 2) (see sect. IIB for details). Thus the skin “talks” to the brain via primary afferents thereby revealing information about the status of peripherally derived pain, pruritus, and local inflammation. Recent studies on the pathophysiology of pruritus reveal the complexity of the bidirectional network be- FIG. 2. Mediators and sensitization pattern of nociceptive and pruriceptive neurons in the skin. Sensitizing and acti- vating mediators in the skin target recep- tors on primary afferent nerve fibers in- volved in itch and pain processing. Dur- ing inflammation, mechanoinsensitive “sleeping” nociceptors and itch hista- mine-sensitive mechanoinsensitive puri- ceptors and probably mechanosensitive puriceptors transmit the response to the spinal cord. In the spinal cord noxious input can induce central sensitization for pain, and puriceptive input can provoke central sensitization for itch. Via the con- tralateral tractus spinothalamicus, the stimuli from primary afferent sensory nerves will be transmitted to specific ar- eas in the CNS (see sect. II for details). 1312 ROOSTERMAN ET AL. Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org by 97.96.42.6 on October 28, 2017 http://physrev.physiology.org/ Downloaded from