Cutaneous innervation and the role of neuronal peptides in cutaneous inflammation: a minireview

ARTICLE

During recent years, neurochemical applications of immunohistochemistry, radioimmunoassay and high-performance liquid chromatography have been used extensively to examine the innervation of human skin (Fig. 1). The skin is innervated by primary afferent sensory nerves, postganglionic cholinergic parasympathetic nerves and postganglionic adrenergic and cholinergic sympathetic nerves. Several neuropeptides have been detected in normal and in pathological human skin, including the nervous system [1-3] (Fig. 2). Unfortunately, it is far beyond the possibilities of this short review to cover all the very elegant and interesting work which has already been published. For a full coverage, we strongly recommend the reader to scrutinize available databases, such as Medline.

Sensory nerves not only function as an afferent system to conduct stimuli from the skin to the central nervous system, but they also act in an efferent neurosecretory fashion through their terminals [4] (Fig. 3). Indeed, noxious stimuli (mechanical, thermal, chemical) may directly activate peripheral endings of primary sensory neurons which are depolarized, and impulses are conveyed centrally as well as, through antidromic axon-reflexes, peripherally. They participate not only in the neurotransmission but also in the regulation of the immune response [5]. Upon release of neuropeptides from sensory terminals, important visceromotor, inflammatory and trophic effects occur in the peripheral tissues [6-11]. This proinflammatory neuropeptide release causes the set of changes collectively referred to as "neurogenic inflammation" [12]. The key components of neurogenic inflammation are the local precapillary vasodilatation, the plasma protein extravasation through pericapillary vessels into the extracellular space of the peripheral tissues, and a leucocyte infiltration that follows antidromic stimulation of peripheral sensory nerves [9, 13-15]. Other agents, such as the peptide bradykinin, derived from plasma proteins, prostaglandins, secreted from tissue cells, and additional factors, released from vascular endothelial cells, such as endothelin and nitric oxide (NO), may contribute to neurogenic inflammation [15]. These nerves are either unmyelinated C-fibers, including both sensory and autonomic ones, or myelinated A delta-fibers [16, 17]. In the skin, the A delta-fibers are preferentially responsible for vasodilatation, whereas the C-fibers are responsible for plasma leakage [18, 19]. Cutaneous nerve fibers can modulate inflammatory reactions through local release of neuropeptides. These neuropeptides are able to regulate both acute and chronic aspects of cutaneous inflammatory processes, such as vascular motility, cellular trafficking, activation and trophism [18-20].

Neuropeptides are a heterogeneous group of several hundred biologically active peptides, present in neurons of both the central and peripheral nervous system and involved in the transmission of signals not only between nerve cells, but also with the immune system where they appear to be critical mediators of different processes.

They act as neuromodulators, neurotransmitters, neurohormones and hormones [21, 22]. In the skin, they are released in response to nociceptive stimulation by pain, temperature, mechanical and chemical irritants to mediate skin responses to infection, injury and wound healing [23, 24].

After release, neuropeptides are metabolized by membrane-bound neutral endopeptidases that are present in many tissues, including skin, and are contained in target structures for neuropeptides [25, 26]. In the course of skin diseases, especially inflammatory diseases, the neuro-immuno-cutaneous system is destabilized. This phenomenon might be due to the inflammation, but it is also responsible for induction and maintenance of the inflammation. In fact, quantitative variations in cutaneous levels of some neuropeptides have been found in lesional skin in a number of dermatoses.

New proposals about neurogenic inflammation

The Working Group on Neurogenic Inflammation proposed 11 testable hypotheses in three domains regarding neurogenic inflammation, namely perceptual and central integration, and non-neurogenic inflammation. This group selected the term "People Reporting Chemical Sensitivity (PRCS)" to identify the primary subject group. In the first domain, the testable hypotheses included: PRCS have an increased density of C-fiber neurons in symptomatic tissues; PRCS produce greater quantities of neuropeptides and prostanoids than non-sensitive subjects in response to exposure to low levels of capsaicin or other irritant chemicals; and PRCS have an increased and prolonged response to exogenously administered C-fiber activators, such as capsaicin. The PRCS group demonstrates augmentation of central autonomic reflexes following exposure to agents that produce C-fiber stimulation; have decreased quantities of neutral endopeptidase in their mucosa; and exogenous neuropeptide challenge reproduces symptoms in PRCS [27].

In the second domain, PRCS have alterations in adaptation, habituation, cortical representation, perception, cognition and hedonics as compared to controls. Also the higher integration of sensory input is altered. In the last domain, PRCS present an increased inflammation in symptomatic tissues associated with a heightened neurosensory response and PRCS show an augmented inflammatory response to chemical exposure.

Neuropeptides and dermatological diseases

There have been many reports on the occurrence of neuropeptides in human skin both under normal (for one of many reviews [28]) and pathological conditions, e.g. calcitonin gene-related peptide (CGRP) in prurigo nodularis [29], vitiligo vulgaris [30] and in psoriasis [31], neuropeptide Y (NPY) in atopic dermatitis [32], in Raynaud's phenomenon and systemic sclerosis [33], substance P (SP) in psoriasis [34-36], atopic dermatitis [32], prurigo nodularis [37], rosacea [38] and in purpuric and/or vasculitic disorders [39], vasoactive intestinal polypeptide (VIP) in atopic dermatitis [40, 41], eczema [42], allergic contact dermatitis [43, 44], lichen sclerosus et atrophicus [45] and psoriasis [11, 42], SP and VIP in psoriasis [46, 47] and in bullous disease [48], somatostatin in urticaria pigmentosa [49, 50], somatostatin and avian pancreatic polypeptide in diabetic lipodystrophic skin [51], CGRP, SP and VIP in dermographism and urticaria [52], CGRP and SP in alopecia areata [53-56] and their contribution to inflammation following ultraviolet irradiation of the skin [57] and, finally, neurokinin A (NKA) in patients with atopic diseases [58] (Fig. 4).

In the near future, most likely, neuropeptides will represent a new approach to skin therapy. An increasing body of evidence supports the setting up of clinical trials using topical neuropeptide agonists and/or antagonists in the treatment of chronic inflammatory skin disorders, such as post-herpetic neuralgia, prurigo nodularis, localized pruritus, psoriasis, atopic dermatitis, contact dermatitis, cold urticaria, notalgia paresthetica, diabetic neuropathy, and Raynaud's phenomenon [59].

In vitro, neuropeptides have different actions on inflammatory cells, including lymphocyte and monocyte chemotaxis, neutrophil activation and cutaneous mast cell degranulation [60-62]. But it is important to underline that some neuropeptides can either enhance or inhibit particular immune/inflammatory cell functions. This "duality" can only partially be explained by dose-dependency and the fact that in a variety of systems, heterogeneous cell population are commonly used. For example, it has repetitively been shown that cell proliferation, immunoglobulin synthesis and natural killer activity could be enhanced, inhibited or not affected at all by such neuropeptides as somatostatin or VIP, depending on the experimental conditions [63].

Peripheral functions of the most important cutaneous neuropeptides

Components of the cutaneous nervous system interact with many types of cells in the skin to mediate important actions in skin inflammation and wound healing [64-66].

SP (discovered in 1931 [67] and isolated and characterized in 1970 [68]) is the best characterized of the neuropeptides released from sensory C-fibers in the skin [69] and its activities require not only secretion, but also the expression of the SP receptor on local target cells as well as expression of tissue proteases that degrade neuropeptides, such as neutral endopeptidase [70]. SP is a member of the tachykinin family together with neurokinin A (NKA; also called neurokinin alpha, substance K or neuromedin L) and neurokinin B (NKB; also known as neurokinin ß or neuromedin K), and is present in many areas of the nervous system, but especially in areas of immunological importance, such as the gastrointestinal tract, the respiratory tract, the eyes and the skin [71]. In the peripheral nervous system, SP occurs in a subpopulation of primary afferent neurons, A delta- and C-fibers, which transmit impulses initiated by noxious stimuli [72]. SP is synthesized in the dorsal root ganglia, from which it migrates centrally to the dorsal horn of the spinal cord and peripherally to e.g. cutaneous nerve terminals of the sensory neurons [69]. There are two SP precursors, the alpha-preprotachykinin and the ß-preprotachykinin, from the second there are the sequence for both SP and NKA, and both share a common spectrum of biological activities [46, 57, 73]. Three distinct receptors, termed NK-1, NK-2 and NK-3, mediate the biological effects of tachykinins, with SP, NKA and NKB as their preferred endogenous agonist, respectively. The peripheral actions where SP is involved is cutaneous neuroinflammation with vasodilatation and increased vascular permeability and promotion of cell proliferation.

SP is one of the most potent vasodilators, and plays a role in the cutaneous weal and flare response following antidromic stimulation of sensory nerves, an effect which can be prevented by pretreatment with capsaicin [74-77]. Vasodilatation is due to a direct action of SP on the vascular smooth muscles [78] and an enhanced production of nitric oxide (NO) by the endothelium [79]. SP can also initiate microvascular permeability and protein extravasation after tissue injury [71, 74, 80]. In fact, intradermal injection of SP increases vascular permeability. SP (and CGRP) are potent releasers of histamine from mast cells [81], an action not dependent on cell-bound IgE, and it has been suggested that in antidromic weal-and-flare reactions, the tachykinins may act directly on the vasculature to increase permeability and to produce weal oedema, but indirectly through the release of histamine from mast cells to produce the flare response [82]. Furthermore, injection of SP into the skin has been shown to mimic the response to that of histamine or the mast cell degranulating compound 48/80. This response was inhibited by antihistamines [83]. NKA is less potent than SP in inducing flare and itch in human skin, and this poor response to NKA may reflect a weak histamine-releasing ability. Nonetheless, the flare evoked by NKA is reduced by pretreatment with compound 48/80 [15, 83].

SP has also been implicated in the modulation of inflammation because the peptide promotes the proliferation of various types of target cells. Both SP and NKA have been shown to stimulate proliferation of human cultured keratinocytes, fibroblasts and endothelial cells [7, 84-86], but under certain circumstances, they instead suppressed keratinocyte growth [11]. In addition, they also stimulate the proliferation of arterial smooth muscle cells, thereby aiding healing processes [7]. In vivo, SP stimulates neovascularization [86] and may modulate melanocyte gene expression, is chemotactic for melanocytes, and can enhance their dendricity, but not as nerve growth factor (NGF) or CGRP [87, 88].

Several secretory peptides belong to the glucagon-secretin family [89], of which the two peptides vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) appear to be the most important in human skin. VIP and PHM have a widespread tissue distribution in the central as well as the peripheral nervous system, and are known to co-localize in peripheral autonomic nerves [90]. In human skin, innervation with nerves containing these peptides, occurs around the glandular cells, ducts and myoepithelial cells of the eccrine sweat glands, where they increase the secretion of sweat [91-94], around the arterial segment of the deep and superficial vascular plexuses, and close to hair follicles [95, 96]. PHM-immunoreactive fibers have also been shown in the vicinity of apocrine glands [97]. VIP is a very important vasodilator agent and intradermal injection of VIP produces rapid vasodilatation and increased vascular permeability; therefore, VIP's primary effects are erythema and sometimes oedema [98]. Furthermore, this peptide plays a role in the regulation of the skin blood flow [99]. Finally, when released from sensory nerve endings and/or mast cells VIP promotes the proliferation of keratinocytes by stimulating adenylate cyclase activity by way of specific VIP receptors [10, 84, 100].

VIP is known to be a potent releaser of histamine into the extracellular space from mast cells, indicating a common pathway of activation from VIP and other histamine-releasing substances, distinct from that of IgE-dependent activation [101, 102]. VIP has anti-inflammatory qualities in that it suppresses delayed hypersensitivity in vitro and inhibits phospholipase A2 [103, 104]. Finally, VIP and pre-pro-VIP-like peptides have been suggested to be involved in the physiological adaptation of central neurons during long-term resting periods [105].

The 37 amino acid peptide, calcitonin gene-related peptide (CGRP; discovered by Amara and colleagues in 1982 [106, 107]), derived from the calcitonin/CGRP gene by alternative RNA splicing, along with the tachykinins SP and NKA, is the major peptide present in primary afferent C-fiber neurons. It occurs in two forms, designated CGRP-alpha or CGRP-1 and CGRP-ß or CGRP-2 [106-108]. In human skin, two CGRP-containing populations of unmyelinated sensory nerve fibers have been visualized, one co-localizing with SP in small-diameter sensory nerves, occurring in the dermal papillae and free epidermal nerve endings of glabrous skin, suggesting that these neuropeptides have a common role in cutaneous sensory innervation. The other co-localizes with somatostatin in a similar fashion in the axons associated with the epidermis and the perivascular space [109-111]. Release of CGRP from efferent neurons contributes to the neurogenic inflammatory response, and it may even be considered the primary mediator of neurogenic vasodilatation. It is an essential mediator of the non-adrenergic non-cholinergic (NANC) vasodilatation both in the gastric mucosa and skin. The vasodilator effect of CGRP is of pathophysiological significance for the protection of the gastric mucosa from injury and for the process of neurogenic inflammation in the skin [112]. Like SP, somatostatin and VIP produce dose-related weal and flare reactions in human skin, but only relatively high doses of CGRP cause weal and flare and these reactions are much weaker than those produced by SP [113]. Intradermally injected CGRP has shown a third type of response in the form of a slowly developing, long-lasting and intense erythema at the site of injection [82, 114-116]. This vasodilatation does not involve the release of histamine from human skin mast cells and the erythema is not suppressed by pretreatment with mepyramine or compound 48/80 or by lidocaine treatment [83].

CGRP also has an important mitogenic effect, increasing endothelial cell proliferation [117, 118] and inducing the expression of endothelial adhesion molecules [119]. Recently, it has been demonstrated that CGRP increases the DNA synthesis rate of melanocytes in a concentration- and time-dependent manner. Furthermore, stimulation by CGRP induced a rapid and dose-dependent accumulation of intracellular cyclic AMP (cAMP), suggesting that the mitogenic effect is mediated by the cAMP pathway and also indicating an intimate relationship between the nervous system and epidermal melanocytes. This may be of great relevance to normal and pathological pigmentation of the skin [88]. CGRP has an important trophic effect in the regeneration of UV-damaged skin [57, 120]. In fact, the CGRP synthesis is also increased after nerve injury, suggesting that this peptide in addition may play a role in nerve regeneration. Indeed, CGRP promotes Schwann cell proliferation through an activation of certain cAMP pathways [121].

Although neuropeptides have been widely implicated in inflammation, detailed mechanisms underlying neuropeptide-induced extravasation of leucocytes from blood vessels into tissue are lacking. This process is central to the development of an inflammatory response and requires adhesion molecule-mediated interactions between the vascular endothelium and circulating leucocytes [122]. Neuropeptide Y (NPY), a 36 amino acid peptide [123], has been shown to coexist with noradrenaline in sympathetic nerves localized around blood vessels in various vascular beds [91]. In the skin, NPY has been identified in the periarteriolar nerve fibers of the deep and superficial dermal plexuses and in basal cells of the epidermis [91, 99], but it was also found to innervate eccrine sweat glands, myoepithelial components of sweat glands and to a lesser degree apocrine, sebaceous glands and hair follicles [93, 124-126]. With this distribution around the cutaneous vasculature, NPY causes vasoconstriction of blood vessels and this vasoconstriction is mediated by Y2 postjunctional receptors [127, 128]. Neuropeptide Y, thus, plays a role in the regulation of skin blood flow, and possibly eccrine sweat production. Finally, NPY has also been demonstrated to modulate adrenergic neurotransmission by an endothelium-dependent mechanism [129].

Specific effects of some important cutaneous neuropeptides
on the immune system

There is also increasing evidence to indicate that neuropeptides may influence the immune response [130, 131]. Neuropeptides seem to be involved in the regulation of lymphocyte activation in organs where immune reactions are initiated, such as the gut, the respiratory tract and the skin [132].

SP has been shown to have important effects on the immune system both in vitro and in vivo. It acts on cellular proliferation with enhanced proliferation and function of B cells concomitant with the production of the two immunoglobulins, IgA and IgM, and T cells [133]. SP has effects on cytokine production and secretion, including enhanced IL-1, IL-6, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma production by monocytes, enhanced expression and secretion of IL-1a, IL-1ra and granulocyte/macrophage colony-stimulating factor by keratinocytes [134], TNF-alpha secretion by mast cells [135], and IL-2 synthesis and secretion by peripheral blood monocyte cells [136]. SP also acts on phagocytosis, enhances the macrophage and polymorphonuclear-leucocyte activity, and acts on the release of histamine, prostaglandin and leucotriene from mast cells [77]. Furthermore, SP influences inflammatory responses by stimulating monocyte and polymorphonuclear leukocyte chemotaxis [137, 138], and is able to directly activate human dermal microvascular endothelial cells to express high levels of the vascular cellular adhesion molecule 1 in a dose-dependent fashion [138].

VIP has been reported to inhibit the proliferation of thymocytes [139], and peripheral lymphocytes after addition of mitogenic lectins [140]. In addition, VIP presents a dual effect on mononuclear and polymorphonuclear leucocyte migration depending on the VIP concentration. A high concentration inhibited, while a low concentration stimulated, mononuclear leucocyte migration [132]. As regards the mechanism for the modulating effects of VIP on leucocyte migration, it has been shown [141] that VIP is an efficient stimulator of cAMP production in mononuclear cells, and this stimulation is observed at concentrations as low as 10^{­ 11} M of VIP and has a maximum at 10^{­ 9} M [132]. In this context, it may be pointed out that Johansson & Madsen [8] have demonstrated proliferative effects on cultured chondrocytes of the peptide somatostatin in the 10^{­ 15} M-range! The inhibiting effect of VIP on leucocyte migration was abolished when VIP was split into C- and N-terminal fragments, while a stimulating effect was retained in the N-terminal fragment. VIP reduces IgA synthesis, stimulates the production of IgM by B cells and inhibits natural killer cell activity [142] and it has an important immunomodulatory role, e.g. by having an inhibitory effect in established allergic contact dermatitis. This effect is possibly mediated through an increased production of interferon-gamma by peripheral blood mononuclear cells [43, 132].

It may be noted, that CGRP has been reported to stimulate the chemotaxis of human T lymphocytes and to inhibit T cell proliferation [143].

Recently, some compounds including SP, NKA, NPY, CGRP, prolactin, serotonin, VIP, somatostatin and thyrotropin releasing hormone (TRH), have been detected in the epidermis in association with Langerhans cells (LCs) (Figs. 5 and 6). NPY was found to be expressed by LCs in atopic lesions and CGRP-containing nerves have been shown to be intimately associated with hemopoietic cells and LCs [144-148]. One important implication is demonstrated by CGRP being able to inhibit LC antigen-presenting capability mediated by an increased IL-10 production by LCs and by down-regulating the expression of accessory molecules, such as B7-2 on the surface of antigen-presenting cells, but not B7-1 [149, 150]. Also, both IL-12 p40 and interferon-gamma levels were found to be decreased. This inhibition could be abrogated by addition of anti-IL-10 antibodies [145, 147]. These data suggest that CGRP inhibits peripheral blood mononuclear cell proliferation, in part through the release of IL-10, which in turn can down-regulate important co-stimulatory molecules and the cytokines IL-12 and interferon-gamma [151, 152]. Finally, CGRP is capable of stimulating human dermal microvascular endothelial cells to secrete the neutrophil chemotactic factor IL-8 [138, 152].

In summary, it is becoming more and more evident that neuropeptides, localized in cells or nerve fibers, are very important for the regulation of cutaneous immunological reactions. It will be a most promising and stimulating task to further elucidate the morphological, functional and pharmacological details of these vast neuropeptide-containing systems of the human skin, with special emphasis on possible interaction mechanisms (Fig. 7).

During the preparation of this paper, we were highly impressed by all the chapters in The Journal of Investigative Dermatology Symposium Proceedings, Vol. 2, 1997, entitled "Cutaneous Innervation and Neurobiology of the Skin" [153], as well as the two recent reviews in Experimental Dermatology, Vol. 7, 1998, entitled "Neuropeptides and Langerhans Cells" and "Neuropeptides in the Skin: Interactions between the Neuroendocrine and the Skin Immune Systems" [154, 155]. We hereby would like to strongly recommend the readers of our paper to also acquaint themselves with these publications.

CONCLUSION

Acknowledgements

This study was supported by grants from the Cancer- och Allergifonden, the Swedish Work Environment Fund (proj. no. 96-0841 and 97-1056), Svenska Industritjänstemannaförbundet (SIF), Sveriges Civilingenjörsförbunds Miljöfond, Vårdalstiftelsen, and funds from the Medical Faculty of the Karolinska Institute. Ms Eva-Karin Johansson and Dr. Yong Liang are gratefully acknowledged for excellent secretarial assistance.

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