DOI:10.1111/j.1600-0625.2007.00670.x www.blackwellpublishing.

com/EXD

Review Article

The skin as a mirror of the soul: exploring the possible roles of serotonin
Klas Nordlind1, Efrain C. Azmitia2 and Andrzej Slominski3
Department of Dermatology, Karolinska University Hospital, Solna, Stockholm, Sweden; Department of Biology and Psychiatry, Center for Neural Science, New York University, New York, USA; 3 Department of Pathology and Laboratory Medicine, University of Tennessee HSC, Memphis, USA Correspondence: Klas Nordlind, MD, PhD, Unit of Dermatology and Venereology, Department of Medicine, Karolinska University Hospital, Solna, SE 171 76 Stockholm, Sweden, Tel.: +46 8 5177 7882, Fax: +46 8 5177 7851, e-mail: Klas.Nordlind@karolinska.se
2 1

Accepted for publication 16 November 2007

Abstract: Serotonin (5-hydroxytryptamine; 5-HT) is an

important mediator of bidirectional interactions between the neuroendocrine system and the skin. The rate of synthesis of 5-HT from l-tryptophan can be enhanced by brain-derived neuronal growth factor, cytokines, exposure to ultraviolet light and steroids. The major source of 5-HT in the skin are platelets, which, upon aggregation, release this biogenic amine. Moreover, the epidermal and dermal skin express the enzymes required for the transformation of tryptophan to 5-HT, and certain skin cells, such as melanocytes, have been demonstrated to produce 5-HT. In addition, rodent mast cells produce 5-HT, but human mast cells have not yet been fully examined in this respect. Skin cells express functionally active, membrane-bound receptors for 5-HT, as well as proteins that transport 5-HT. The interactions of 5-HT with these various proteins determines the nature, magnitude and duration of serotonergic responses.

The immune and vasculature systems in the skin are traditional targets for bioregulation by 5-HT. Moreover, recent ndings indicate that keratinocytes, melanocytes and dermal broblasts also respond to this amine in various ways. Thus, mammalian skin is both a site for the production of and a target for bioregulation by 5-HT. This indicates that agonists and antagonists directed towards specic 5-HT receptors could be useful in connection with treatment of skin diseases. Based on our increasing knowledge concerning these receptors and their plasticity, future research will focus on the development of serotonergic drugs that exert metabotrophic effects on the cells of the skin without affecting the central nervous system.
Key words: 5-HT 5-HT receptors 5-HT transporters skin

Please cite this paper as: The skin as a mirror of the soul: exploring the possible roles of serotonin. Experimental Dermatology 2008; 17: 301311.

Introduction
The skin can be considered to be a mirror of the soul. Light from the outside world passes through the layers of epidermal cells, the rst line of immune defenses, and then interacts with the neuroendocrine system. The dynamic interactions between these two extensive systems involve many molecules (1), among which serotonin (5-hydroxytryptamine; 5-HT) is of major importance. Synthesised from l-tryptophan, 5-HT was originally named tonin on the basis of its capacity to regulate the tonus of blood vessels (2). Distributed widely throughout the body, this signal molecule plays important roles in connection with stress responses, appetite, sleep, sexual desire, memory and behaviour (3). As 5-HT is synthesised in the skin, its role in cutaneous physiology and pathology, e.g. in regulation of inammatory processes, is also receiving more and more attention.

The broad distribution of 5-HT in living organisms, including the central and peripheral nervous tissues of mammals, is indicative of a central role in maintaining homeostasis (3). 5-HT in the plasma, brain and various other organs integrates the effects of signals from sensory and motor systems, as well as endocrine, digestive, immunological and vascular signals on the various cells in the human body. Steroids, neuropeptides and growth factors can also inuence production and secretion of 5-HT by serotonergic cells. Consequently, alterations in the levels of 5-HT in extracellular uids can alter the maturation, metabolism, migration and mitosis of its target cells, including those in both the brain and the skin. The purpose of the present review is to highlight the importance of 5-HT as a signalling substance that mediates neurocutanous interactions, both at the organ and cellular levels. In addition, questions regarding 5-HT and the skin

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are posed and future directions in this important area of research on skin physiology envisioned.

Synthesis and general and cellular effects of 5-HT

Synthesis of 5-HT starts with hydroxylation of the l-tryptophan at the fth position on the indole ring to yield 5-hydroxytryptophan (TrpOH; Fig. 1). This reaction requires molecular oxygen and the reducing cofactor 6-tetrahydrobiopterin and is catalysed by tryptophan hydroxylase (TPH), an enzyme encoded by the TPH1 (which is expressed ubiquitously) and TPH2 genes (expressed predominantly in the brain) (4,5). Thereafter, TrpOH is decarboxylated to produce 5-HT in a reaction catalysed by the ubiquitously expressed l-aromatic amino acid decarboxylase (AAD) and involving the cofactor pyridoxal phosphate. These enzymes that synthesise 5-HT appeared very early during evolution (6). Tryptophan, the amino acid precursor for 5-HT, captures light with great efciency and is present in the reactive core of chlorophyll (6,7). Consequently, plants have a highly efcient mechanism for synthesising tryptophan within chloroplasts and also produce high levels of 5-HT. This 5-HT serves as a trophic factor involved in root growth and leaf motility, as well as a potent antioxidant. Lacking chloroplasts, animals also lack the ability to synthesise tryptophan and must, therefore, obtain this amino acid from dietary sources (8). Although overall levels of 5HT are, therefore, lower, its trophic and antioxidation functions are similar in animals (7). In the plasma of mammals, tryptophan is present at steady state both in the free form (at a concentration of approximately 12 lm) and tightly bound to serum albumin (about 61 lm) (9). The free form can enter cells, including those of the brain. Its level exhibits diurnal and seasonal

variations and is also inuenced by diet and stress, as well as by age and gender. TPH, the rate-limiting enzyme in 5-HT biosynthesis, has a dissociation constant (Kd) for tryptophan of approximately 10)8 m, i.e. close to the free level in serum, so that uctuations in this free pool can directly and immediately alter the amount of 5-HT that is produced. Tryptophan hydroxylase is expressed by brainstem neurons and in the pineal gland, lung, gut and skin. In the case of skin, this enzyme is localised in blood vessels, mast cells, melanocytes, keratinocytes and broblasts (10,11), where 5-HT may function as an antioxidant, as well as inuencing cellular metabolism. Activated T cells also express TPH1 and the 5-HT they produce is taken by dendritic cells, which also receive 5-HT from other sources in their microenvironment (12). The mast cells of rodents (13), dogs (14) and guinea pigs (15) contain 5-HT, whereas the presence of this compound in human mast cells has only been reported occasionally (10,1618). Interestingly, mast cells in the thalamic nuclei of the rat brain, which appear to modulate neuronal activity, also contain 5-HT (19).

Biochemical and molecular biological aspects of 5-HT synthesis in the skin

Tryptophan hydroxylase 1 mRNA with the expected sequence has been detected in biopsies of normal human skin, as well as in basal cell carcinomas, normal epidermal and follicular melanocytes in culture, melanoma cell lines, normal neonatal, adult epidermal and follicular keratinocytes, squamous cell carcinoma cells and follicular and dermal broblasts (20). In addition, aberrant species of TPH1 mRNA are present in keratinocytes from a human cell line (HaCaT), melanoma cells (20) and mastocytoma cells (21). The levels of TPH protein in extracts of skin or of normal or malignant epidermal keratinocytes and melanocytes or dermal broblasts have been examined with Western blotting (10,11). The size variability detected in the skin indicates extensive turnover of this enzyme in this tissue (11). Immunocytochemical analysis of skin biopsies xed in paraformaldehyde or formalin revealed that TPH and 5-HT are localised primarily in normal melanocytes and malignant melanoma, suggesting that the pathway for 5-HT synthesis is expressed predominantly in the melanocytic cells of this tissue (11,22). However, more recent immunouorescence studies on biopsies of human scalp detected TPH in the epidermis and adnexal structures as well (10). Moreover, AAD mRNA was found in epidermal keratinocytes and melanocytes and the protein itself in melanocytes (23). In addition, of relevance in this connection is the observation that the skin is fully capable of

Figure 1. Schematic illustration of the biosynthesis of 5-HT. Starting from tryptophan, this synthesis proceeds via reactions catalysed by two enzymes, TPH and l-aromatic AAD. The rst of these steps has been clearly shown to be rate limiting.

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synthesising 6-tetrahydrobiopterin, the cofactor required for TPH activity (24). Of direct relevance to these ndings is the detection of the enzymatic activity of TPH in extracts of skin cells, of 5-HT itself in skin cells and extracts, and of both 5-HTP and 5-HT in melanoma cell (10,11,20,25). In addition, positive immunohistochemical staining for 5-HT is exhibited by the epidermal and adnexal compartments and by mast cells in the skin (10,16,18). The enzymes required to synthesise 5-HT from tryptophan are also present in the skin of rodents (reviewed in 10). For example, the TPH gene (Accession No. AY034600) is expressed in hamster skin and melanoma cell lines, as well as in the spleen and liver of this rodent (26). Similarly, the mouse TPH gene (Accession No. NM_009414) is expressed in the skin of this animal during all phases of the hair cycle, with the lowest level being present in the telogen phase, as well as in cultured mouse follicular melanocytes and melanoma cells (27). The TPH expressed in the mouse demonstrates a band with the expected molecular weight 5355 kDa upon Western blotting. However, larger and smaller bands were also detected and it was proposed that the high molecular weight immunoreactive species reects ubiquitinated TPH, whereas the smaller species represent degradation products. Finally, biochemical assays have documented the conversion of tryptophan to TrpOH in hamster melanoma cells and, furthermore, 5-HT itself was detected in extracts of these cells by reverse-phase high-performance liquid chromatography (RP-HPLC) and liquid chromatography mass spectrometry (LC MS) (26).

Figure 2. Synthesis, storage, release and reuptake of 5-HT at synaptic and non-synaptic nerve endings. The actions of 5-HT are regulated by changes in the local rate of synthesis of this compound in response to alterations in the availability of tryptophan, molecular oxygen and or reduced biopterin. 5-HT can be released from nerve cells by a Ca++mediated mechanism involving vesicles or by the reverse action of 5HTT (28). A large number of drugs designed to interfere with all of the individual steps involved in local release and reuptake of 5-HT, as well as binding of this compound to its receptor, have been developed.

Release and reuptake of 5-HT

In the plasma, 5-HT can be taken up into platelets by a 5-HT transporter (5-HTT). This protein, with its 12 membrane-spanning domains, can both release 5-HT and reuptake this signal molecule (28) although under most conditions reuptake is favoured. A large number of pharmacological drugs referred to as specic serotonin reuptake inhibitors (SSRIs) inhibit the reuptake process (Fig. 2). At the same time, drugs such as 3,4 methylenedioxymethamphetamine (ecstasy) (MDMA) and methylamphetamine are potent inhibitors of the release of 5-HT from platelets via 5-HTT. Platelet levels of 5-HTT exhibit seasonal variations (29). Furthermore, genetic polymorphisms in the promoter as well as in intron regions of the 5-HTT gene render the individuals involved more prone to stress and depression (30,31). It has been proposed that the brains of subjects with inactivating polymorphisms take up lower amounts of 5-HT, but the eventual signicance of this process for peripheral cells is unclear (32).

The release of 5-HT by melanocytes and mast cells may inuence cell communication in the periphery. Although this release by mast cells has been postulated to involve intracellular granules and is probably regulated by Ca++ inux, release of cytoplasmic 5-HT through the reuptake protein is certainly possible and such a process would be regulated by the concentrations of 5-HT inside and outside the cell (28,3335). 5-HT is also released by Merkel cells, highly specialised cells that receive many axon terminals, can be activated by mechanical reception and or distortion and indirectly regulate the action of sensory neurons via 5HT1A receptors (36,37). Both Merkel cells and their axon terminals express 5-HTT (37,38).

Serotonin receptors
Free 5-HT can interact with specic cell surface membrane-bound receptors (R) which are classied into seven general families (3941). These receptors are coupled to G-proteins and can stimulate (5-HT7R) or attenuate (5-HT1R) adenylate cyclase activity or enhance the activity of phosphoinositol (PI)-hydrolases (5-HT2AR). In addition, 5-HT3R can function as an ion channel. As observed in the brain (7), 5-HT receptors may act in a competitive manner. For example, via 5-HT1AR 5-HT can reduce intracellular levels of cyclic AMP (c-AMP) and calciumlinked kinase activity, whereas activation of 5-HT7R can

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increase c-AMP levels. The net result determines the degree of phosphorylation of the c-AMP response element-binding protein (p-CREB), an important transcription factor in connection with development and maintenance of adult homeostasis (42). Through their C-terminus and or intracellular loops, several 5-HTR subtypes interact sterically with calmodulin and such interaction can modulate the phosphorylation and consequent desensitisation of the activated receptor (see 41). Interestingly, antagonists of calmodulin ameliorate the symptoms of skin diseases associated with increased levels of 5-HT (43). It should here also be mentioned that S100b protein, a closely related molecule to calmodulin, is expressed in inammatory skin diseases and disturbed epidermal maturation (44). Monoamines, including 5-HT, serve as neuronal growth factors to induce maturational, protective and metabolic changes (7,45). The 5-HT1A receptor has long been shown to produce trophic changes by acting through a glial-mediated release of S100b (7,46,47). S100b containing astrocytes are signicantly increased in the brains of mice with overexpression of the 5-HT1A receptor gene (48). Not only does the 5HT1AR produce changes in neuronal maturation rate but serves an antiapoptotic factor (4951). Activation of the 5-HT1AR in neuronal and hippocampal HN2-5 cells attenuates the activation of caspase-3 induced by anoxia, an effect that is apparently mediated by phospholipase C (PLC) via a pathway suggested to be dependent on the extracellular-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) a (52). An activation of NF-jb by a 5-HT1AR agonist has also been shown for activated B and T cell splenocytes, promoting their survival and proliferation (53). The afnity of 5-HT1AR for 5-HT is sufciently high for it to be stimulated by normal daytime circulating levels of this ligand. Furthermore, expression of this receptor is down-regulated by prolonged activation (5456). In contrast, the 5-HT2AR is a low-afnity receptor activated only by high levels of 5-HT (i.e. about 100-fold above normal circulating levels). Activation of this receptor promotes hydrolysis of PI and an increase in intracellular Ca++ levels, thereby stimulating kinase activity, cell division and apoptosis (7,57). Certain evidence indicates that these receptors are involved in physiological functions of the skin. For example, cultures of human skin and skin cells express receptors for 5-HT (10,58,59), as well as the mRNA species that code for 5-HT1A, -1B, -2A, -2B, -2C and -7 (59). Additional investigations in situ have demonstrated expression of 5-HT1AR by basal epidermal melanocytes and of 5-HT2AR in the epidermis of normal and eczematous human skin (58). Moreover, 5-HT3 is expressed in the proliferative basal

layer of the epidermis. In general, with the exception of the immunocytochemical detection of 5-HT3R, the in situ ndings are consistent with molecular analyses in vitro.

Other factors that inuence the action of 5-HT

The functioning of the 5-HT system is also inuenced by cytokines. The enzyme indoleamine 2,3-dioxygenase is expressed by a variety of cells, including macrophages and dendritic cells derived from monocytes, and is induced preferentially by the Th1-type cytokine interferon (IFN)-c. This enzyme reduces intracellular levels of both tryptophan and 5-HT, which contributes to the cytostatic and antiproliferative activity of IFN-c (60). Treatment of cancer patients with cytokines is often associated with depression that is proposed to be caused by the potent reduction of cellular levels of tryptophan and can be alleviated by treatment with SSRIs (61). In addition, pro-inammatory cytokines are known to alter the metabolism and release of 5-HT in the central nervous system by rapidly regulating neuronal 5-HTT activity via p38 MAPK-linked pathways (62). Signicantly, interleukin (IL)-1b receptors and 5-HT2CR demonstrate identical distributions in the medial hypothalamus (63). The possibility of a reciprocal relationship between IL-1 and 5-HT is of interest in the context of our observation of immunohistochemical staining for 5-HT2CR in Langerhans-like cells of the murine skin (64). The brain-derived neuronal growth factor (BDNF) produced by the brain promotes the survival and sprouting of local 5-HT neurons (65,66). Furthermore, reduction of the plasma level of tryptophan gives rise to a signicant increase in the plasma level of BDNF (67). The authors propose that peripheral changes in BDNF levels may reect central processes, as rapid passage of this factor across the blood-brain barrier is mediated by a saturable transport system with high capacity, so that the levels of this compound in the serum and cerebrospinal uid are similar. Moreover, nerve growth factor (NGF), which possesses a structure similar to that of BDNF, stimulates release of 5-HT by mast cells in the rat peritoneum designed to ameliorate inammation and hasten tissue repair (68). Another member of the NGF family, neurotrophin 3 (NT-3), does not induce synthesis of 5-HT in suspension of mast cells (69). In addition, stress activates the hypothalamicpituitary adrenal (HPA) axis, which results in elevated levels of circulating glucocorticoids (70), that stimulate the synthesis and turnover of 5-HT (71,72). Treatment with dexamethasone, a synthetic adrenal steroid, enhances the level of the TPH protein in brainstem neurons (73). In the periphery of patients exhibiting elevated serum levels of cortisol, the

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turnover of 5-hydroxyindole acetic acid (5-HIAA) and 5-HT is abnormally rapid (74). Furthermore, 5-HT1AR levels decrease acutely in connection with stress, a phenomenon that is either because of the direct action of cortisol on gene transcription (75) and or feedback inhibition (55). Chronic stress may have impact on the skin barrier, thereby worsening inammatory skin diseases such as atopic eczema (76). As 5-HT1AR is expressed in the outer part of the epidermis (58), a change of this receptor in chronic stress or during application of glucocorticoids might modulate the protective function of this barrier. Finally, exposure to ultraviolet light enhances the serum concentration of 5-HT via a mechanism that remains to be elucidated (77).

(64). Interestingly, this is the same type of 5-HT receptor that predominates in human skin (59). In addition, 5-HT, also at near-physiological concentrations, modulates cell proliferation in cultures of murine keratinocytes (83), whereas the metabolites NAS and 5-methoxytryptamine (5-MT) stimulate and inhibit melanoma cell proliferation, respectively, only at close to mm concentrations (84).

Degradation of serotonin in the skin

Monoamine oxidase (MAO), which is also expressed in mammalian skin (10), deaminates 5-HT to yield 5-hydroxyindole acetaldehyde, which is then transformed to 5-HIAA and 5-hydroxytryptophol (5-HTPOL) (as demonstrated by LC MS analyses of rodent skin extracts) (27,85). Inhibition of MAO by pargyline attenuates the production of 5-HIAA and 5-HTPOL in rodent skin, thereby conrming the involvement of this enzyme in this production. While both 5-HIAA and 5-HTPOL are formed in mouse skin (27), 5-HIAA is the major degradation product in rat skin, where the level of 5-HTPOL is below the limit of detection (85). Detection of 5-HT and 5-HIAA in human HaCaT keratinocytes (20) suggests that similar metabolism of 5-HT occurs in human skin. Moreover, the presence of 5-methoxytryptamine (5-MT) in both human (25) and rodent (86) skin indicates direct or indirect metabolism of 5-HT to 5-MT. In addition, certain ndings suggest that human and rodent skin transform 5-HT to melatonin via a sequence of reactions (8789).

Actions of 5-HT in the skin

Addition of 5-HT to the medium of cultures of skin cells exerts variable effects on the proliferation of these cells (59). This factor stimulates the growth of dermal broblasts in a dose-dependent manner, whereas in the case of immortalised epidermal melanocytes, 5-HT stimulates growth in the absence of melanocyte growth factors, but inhibits cell proliferation when these factors are present. It has been proposed that these differing effects reect the inuence of 5-HTR on both cell proliferation and apoptosis. Moreover, in a human melanoma cell line, 5-HT inhibits melanogenesis (78), whereas inhibitors of 5-HT uptake prevent the melanisation of melanoma cells (79). These ndings suggest that 5-HT affects melanocyte behaviour (10). The biosynthetic enzyme TPH was shown earlier to be present in mouse mastocytoma (80) and later, 5-HT1AR was found to be expressed in human mastocytoma (Ritter et al., unpublished observations). In addition, 8-hydroxy-2di-n-propylamino-tetralin (8-OH-DPAT), an agonist of 5-HT1AR, reduces the spontaneous release of histamine from a human mast cell line (HMC)-1. Moreover, 5-HT and the 5-HT1A and 5-HT2A receptors, and 5-HTT, are all expressed in benign compound nevi, dysplastic nevi and malignant melanoma (Naimi-Akbahr et al., unpublished observations). The mRNA species coding for the 5-HT2B and 5-HT7 receptors have been demonstrated to be present in samples of mouse and hamster skin (81). In the case of mouse skin, expression of these transcripts varies during the cycle of hair growth, being expressed in anagen, but not in telogen skin (81,82). 5-HT2BR mRNA was found in mouse and hamster melanomas, as well as in immortalised mouse follicular melanocytes, whereas the mRNA for 5-HT7R transcript was detected in hamster melanomas, but not in cultured mouse melanocytes or melanoma cells (81). I-A antigen positive cells in murine epidermis demonstrate positive immunohistochemical staining for 5-HT2CR

Skin pathology: role of 5-HT in skin inammation

Analysis by HPLC has revealed that serum levels of 5-HT in patients with allergic contact eczema are elevated (90), whereas immunohistochemical examination demonstrated that melanocytes expressing 5-HT in the inamed skin of these patients are abnormally elongated. In contrast, 5-HT levels in murine skin undergoing contact allergic reactions are the same as in control skin although the platelets of the allergic animals do exhibit elevated immunohistochemical staining for 5-HT (91). Other immunohistochemical studies have demonstrated elevated expression of 5-HT in the epithelial and adnexal structures of skin suffering from psoriasis (92) or chronic eczema (93), but no such increase in the mast cells in these same samples. Cells that express 5-HT1AR and stain positively for tryptase are diminished in number in association with allergic contact eczema (58,94) and psoriasis (95), whereas the number of dermal cells expressing 5-HT2AR and CD3 is enhanced in connection with both of these inammatory conditions, as well as with atopic dermatitis (96).

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5-HT1AR

Figure 3. Expression of the 5-HT1AR in the apical epidermis, melanocytes (arrowhead points at a typical cell) and mast cells (arrow) of atopic eczematous human skin.

Moreover, 5-HT1AR is also expressed in the apical region of the epidermis, where it might play a role in establishing the skin barrier, and on melanocytes (Fig. 3). 5-HT2CRand I-A positive cells, are increased in number in the epidermis of Balb C mice with contact eczema and, furthermore, an agonist of 5-HT2CR aggravates a contact allergic reaction in the same strain of mice (64). In addition, eczematous human skin contains abnormally large numbers of dermal cells that express 5-HTT, CD3, CD56 as well as exhibiting epidermotropism (94,96). An increase in the number of 5-HTT-positive mononuclear cells has also been observed in patients with psoriasis, both in the affected and unaffected skin, in comparison with normal skin (unpublished observations).

Biological effects of 5-HT in connection with skin inammation

It is questioned which cells that are in control of skin immunity under physiological circumstances (97). Nevertheless, 5-HT mediates important signals in connection with immune responses (98). Specically, 5-HT participates in the activation of T cells and natural killer cells by macrophages; the initiation of delayed-type hypersensitivity responses; the production of a variety of chemotactic factors; and the modication of innate immune responses. Both mast cells and platelets produce 5-HT that may help initiate contact hypersensitivity in normal mice (99). The chemoattractive potency of 5-HT for eosinophils in different mammalian species is probably mediated via the 5-HT2AR and can be blocked by cyproheptadine (100). The enhancement of mast cell migration and adherence

that occurs in response to activation of 5-HT1AR by 5-HT does not involve degranulation. This more pronounced migration is associated with polymerisation of actin and suggests that 5-HT promotes inammation by recruiting mast cells to the site of tissue injury (101). 5-HT receptors also play a role in certain reactions of the skin to light. For example, cis-urocanic acid, produced in response to sunlight, exerts its immunosuppressive effects via binding to both a specic receptor and the structurally similar 5-HT2AR. This immunosuppression might have an impact on the development of skin cancer (102,103). However, it has also been proposed that cis-urocanic acid and 5-HT mediate UVB-induced immunomodulation via independent pathways (104). Earlier, 5-HT1AR was reported to be involved in skin inammation in rats (105). Thus, topical or oral administration of buspirone, an unselective agonist of this receptor, diminishes the severity of contact allergy in these experimental animals. In addition, tandospirone, an agonist of this same receptor, reduces the stress level and attenuates itching in patients with atopic dermatitis (106). Treatment with antagonists of 5-HT2AR reduces the severity of contact allergic reactions in mice (107) and the same effect can be achieved by systemic or topical administration of spiperone (108). In addition, ketanserin, a 5-HT2R antagonist, inhibits the established (109), but not challenge-induced (110) phases of allergic contact dermatitis evoked by nickel in humans. When injected intradermally, 5-HT gives rise to pruritus in human skin (111113), a response that may be mediated via different receptors. For instance, ondansetron, an antagonist of 5-HT3R, reduces the severity of this pruritus (112). Furthermore, the 5-HTT inhibitor paroxetine has been used in the treatment of pruritus associated with malignant disease and its antipruritic action is connected with down-regulation of 5-HT3R expression (114). The 5-HT2AR is present on primary sensory afferents in rat skin (115) and cutaneous 5-HT2AR is at least partially responsible for mediating scratching in mice (113). Primary nerve afferents are proposed to be targets for mediators released by cutaneous cells in response to stimulation by 5-HT. Nonetheless, intradermal injection of 5-HT into rats elicits enhanced c-fos-like immunoreactivity in supercial lamina at the lateral aspect of the dorsal horn, in a manner similar to the immunoreactivity evoked by capsaicin (116). Neither the 5-HT2 nor 5-HT3 receptors are involved in scratching of itches caused by allergic skin dermatitis in rats (117). On the contrary, acute scratching induced by 5-HT is mediated by peripheral 5-HT2 receptors. In contrast to histamine, intradermal injection of 5-HT induces itching in normal, but not inamed skin (118).

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Interestingly, the scratching behaviour induced in hairless (HR-1) mice by 5-HT is more intense than in other mouse strains, such as NC Nga (119,120) and Balb C (120) mice. In addition, HR-1 mice scratch themselves more in response to exposure to compound 48 80 than do NC Nga mice (120). Inhibitors of 5-HTT exert various side effects on the skin including spontaneous bruising, pruritus, urticaria, angioedema, erythema multiforme, the StevenJohnson syndrome, toxic epidermal necrolysis, erythema nodosum, alopecia, hypertrichosis, leukocytoclastic vasculitis and acneiform eruption (121). In addition, ares of psoriasis vulgaris (122,123) have been described in patients administered such compounds. Delayed hypersensitivity has also been noted (124).

Major remaining questions

(1) The serotonergic system displays a high degree of plasticity and novel receptors for 5-HT might have important functions. Does 5-HT evoke pharmacological responses by immune cells in the skin that are similar to the response of neuronal cells? (2) The serotonergic system might be a double-edged sword, even when the same receptor such as 5-HT1AR is involved, modulating the barrier provided by the skin and, at the same time, possibly promoting inammation by prolonging the lifespan of inammatory cells such as mast cells. In this context, the possible ability of SSRI compounds to affect the frequency of apoptosis among immune cells might be of interest, in connection with the treatment of cutaneous inammations. There is a need for study of signalling pathways for the different 5-HT receptor subtypes in various immune cells, and in particular, to establish any relationship with S100b function in the skin. (3) Through evolution, has the serotonergic system been adjusted to the development of the entire immune system, or ne-tuned to innate immunity? In this sense, is there any difference between neuronal cells and the immune cells in the skin? (4) As for other mediators of pruritus, it would be of interest to determine whether serotonergic compounds affect sensory afferents directly and or via their actions on other types of skin cells. In this respect, an in vitro system using human spinal ganglia might be of high interest. This question is especially interesting in the light of the fact that, depending on the strain and species, 5-HT can promote or antagonise the development of pruritus. In this connection, in vitro studies on human spinal ganglia might provide valuable information. (5) The use of different xation procedures (125) may explain the varying reported ndings concerning the content of 5-HT in human mast cells. However, during the

process of evolution, a substantial decrease in this content appears to have occurred and it would be interesting to examine this phenomenon in more detail. (6) Is there any relationship between the state of maturity of mast cells and the level at which they express 5-HT1AR? Which subpopulations of mast cells can store and secrete 5-HT? (7) Assessment of serotonergic transmission in the periphery is problematic. At present, measurement of 5-HIAA levels in the urine is regarded as optimal in this respect, but development of more direct approaches would be of value. (8) Mouse strains in which the genes encoding 5-HT receptors and or 5-HTT have been knocked out provide valuable insights into inammatory skin conditions. It would be of interest to investigate the effects of serotonergic agents on the development of melanoma or other skin tumors in these animals. However, the fundamental differences between murine and human skin, as well as the fact that mice have fur and are also a nocturnal species, while human skin is continuously exposed to solar radiation, should not be forgotten.

Figure 4. Postulated involvement of 5-HT in the biology and pathology of the skin. 5-HT is synthesized by epidermal melanocytes (me), Merkel cells (Me) and inammatory cells such as mast cells (M) in the skin. An additional important source of dermal 5-HT is via release from platelets. Through its effects on keratinocytes (KC), melanocytes and mast cells via the 5-HT1AR, 5-HT may inuence the differentiation and life-span, as well as dendricity, of various types of skin cells. Human melanocytes also express 5-HT2CR (unpublished results). Activation of 5-HT2AR on T lymphocytes (T) probably renders these cells more mobile, allowing them to pass through the basal membrane. Furthermore, this same receptor, together with 5-HT1AR and 5-HT7R, is expressed on vessels and brocytes (FC). 5-HT2CR is expressed by Langerhans cells (LC), where it participates signicantly in determining dendriticity. 5-HTT is also expressed on Langerhans cells (95), as well as on T lymphocytes and Merkel cells, and may, via uptake of 5-HT into these cells, exert an important inuence on their susceptibility to apoptosis. Dendritic cells in the epidermis may also take up 5-HT from the epidermis. The 5-HT2AR present on sensory afferent nerves may inuence nerve transmission and play a role in connection with pruritus. 5-HT3R is expressed by basal keratinocytes and has been reported to be involved in the proliferation of these cells.

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(9) As 5-HT1AR is expressed by mast cells and melanocytes, it would be of interest to look for possible interactions between 5-HT and oncogenes such as c-kit.

Future perspectives: use of drugs

The serotonergic system delivers relatively high concentrations of bioactive molecules to a variety of specic and well-dened targets (Fig. 4). Development of novel serotonergic drugs that are more specic for individual 5-HT receptors represents an intriguing approach to the treatment of inammatory dermatoses and skin tumors. Moreover, seasonal variations in 5-HTT activity (which is higher in winter), that might alter the lifespan of inammatory cells in the skin, as well as genetic polymorphisms in the 5-HTT gene and or alternative splicing of the primary transcript, might be of signicance in connection with the development of such pathological states. Our understanding of the 5-HT receptors, their signal transduction in neuronal and other cells, and the functional consequences of their interactions with accessory proteins needs to be improved. Therapeutic strategies should aim at developing drugs that disrupt or reinforce such interactions in the skin, while exhibiting fewer side effects than those in association with treatment involving classical agonists- or antagonists-based thought to act on the brain. Serotonergic drugs are commonly administered systemically, but topical treatment might also be benecial, as has already been demonstrated in the case of agonists of 5-HT1AR. In this respect, novel serotonergic agents which penetrate across the blood-brain barrier poorly might be useful, as the side effects of such drugs would be expected to be less severe.

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