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Review Biomol Ther 20(6), 506-512 (2012)

Neuroimmunological Mechanism of Pruritus in Atopic Dermatitis Focused on the Role of

Kwangmi Kim*

College of Pharmacy, Dankook University, Cheonan 330-714, Republic of Korea

Abstract Although pruritus is the critical symptom of atopic dermatitis that profoundly affect the patients’ quality of life, controlling and management of prurirtus still remains as unmet needs mainly due to the distinctive multifactorial pathogenesis of pruritus in atopic dermatitis. Based on the distinct feature of atopic dermatitis that psychological state of patients substantially infl uence on the intensity of pruritus, various psychotropic have been used in clinic to relieve pruritus of atopic dermatitis patients. Only several psychotropic drugs were reported to show real antipruritic effects in atopic dermatitis patients including naltrexone, - epin, , , tandospirone, and fl uvoxamine. However, the precise mechanisms of antipruritic effect of these psychotropic drugs are still unclear. In human skin, serotonin receptors and protein are expressed on skin cells such as keratinocytes, melanocytes, dermal fi broblasts, mast cells, T cells, natural killer cells, langerhans cells, and sensory nerve endings. It is noteworthy that drugs, as well as serotonin itself, showed immune-modulating effect. Fenfl uramine, fl uoxetine and 2, 5-dimethoxy-4-iodoamphetamine signifi cantly decreased lymphocyte proliferation. It is still ques- tionable whether these serotonergic drugs exert the immunosuppressive effects via serotonin or serotonin transporter. All these clinical and experimental reports suggest the possibility that antipruritic effects of selective serotonin reuptake inhibitors in atopic dermatitis patients might be at least partly due to their suppressive effect on T cells. Further studies should be conducted to elucidate the precise mechanism of neuroimmunological interaction in pruritus of atopic dermatitis.

Key Words: Pruritus, Atopic dermatitis, Neuromediator, Serotonin, T cells

Pruritus is defi ned as an unpleasant sensation eliciting the Craig, 2001; Paus et al., 2006; Handwerker and Schmelz, urge to scratch. It is one of the signature symptoms in infl am- 2009). Pruritus can be triggered by various endogenous and matory skin diseases. Atopic dermatitis (AD) is one of the exogenous stimuli via free endings of specifi c nonmyelinated, most pruritic skin diseases and pruritus is an essential feature slow-conducting C-type nerve fi ber in the epidermis and der- in diagnosis and treatment of AD (Koblenzer, 1999). Long- mis (Ständer et al., 2002). The stimuli run along the dorsal root lasting pruritus has a profound impact on the patients’ qual- ganglion via the spinal cord and reach different areas of the ity of life (Metz et al., 2011). In many cases, patients scratch cortex, where the scratching refl ex is initiated. the skin lesions to cause erosions, ulcerations, bleeding, and A number of reports indicated that skin immune system is lichenifi cation which can aggravate AD symptoms in turn. The closely related to the provocation and intensity of pruritus in sleep disturbances following prolonged nocturnal scratching AD patients. In this review, the neuroimmunological mecha- and psychological diffi culties such as cicatrization and social nism of pruritus in AD would be discussed based on the re- isolation also result in dramatic impairment in the quality of life ports about the antipruritic effects of several psychotropic in AD patients (Buske-Kirschbaum et al., 2001). Thus, proper drugs, especially focused on the role of serotonin in skin. treatment of pruritus is the critical part of therapeutic approach to AD. Based on early studies, pruritus was regarded as a low- SPECIFIC FEATURES OF PRURITUS IN ATOPIC DER- intensity pain for a long time. Nowadays, it is clear that the MATITIS sensation of pruritus is distinct from the sensation of pain and there exists a sensory system for pruritoception that is dif- Although the pathophysiology of pruritus in AD has not ferent from the sensory system for nociception (Andrew and been fully defi ned yet, a number of reports demonstrated that www.biomolther.org Received Sep 24, 2012 Revised Oct 14, 2012 Accepted Oct 16, 2012 Open Access http://dx.doi.org/10.4062/biomolther.2012.20.6.506 *Corresponding Author pISSN: 1976-9148 eISSN: 2005-4483 E-mail : [email protected] Tel: +82-41-550-1436, Fax: +82-41-559-7899 Copyright © 2012 The Korean Society of Applied Pharmacology

506 Kim. Neuroimmunological Pruritus in Atopic Dermatitis

pruritogenic mechanisms involved in AD are different from as glucocorticoids, cyclosporin A and topical calcineurin in- those of normal pruritus. The skin lesions of AD often have in- hibitors (tacrolimus and pimecrolimus) (Wahlgren et al., 1990; creased density of cutaneous nerve fi bers (Tobin et al., 1992; Hoare et al., 2000; Hanifi n et al., 2001; Luger et al., 2001). Urashima and Mihara, 1998). AD lesional and nonlesional These immunomodulating therapies applied in AD often suc- skin showed increased substance P-positive and calcitonin ceed in reducing pruritus via suppressing the infl ammatory related peptide (CGRP)-positive fi bers associated with mechanisms underlying the induction of pruritus (Yosipovitch increased -nerve fi ber contacts (Järvikallio et al., et al., 1996). The reports that cyclosporin A treatment reduced 2003; Elenkov, 2004). In addition, the skin of AD patients have pruritus in AD patients clearly showed that interleukin-2 and T reduced pruritus threshold and prolonged pruritus duration to cells are at the center of AD pruritus (Wahlgren et al., 1990). pruritic stimuli as compared with healthy skin, resulting in a Even a single intracutaneous injection of IL-2 resulted in inter- higher tendency to pruritus upon stimulation (Morren et al., mittent local pruritus perception in AD patients (Wahlgren et 1994). al., 1995; Darsow et al., 1997). So far, many laboratory and clinical data indicated that a number of genetic, environmental and psychological factors are related to pruritus in AD (Pastar et al., 2005; Weidinger et ROLE OF SKIN T CELLS IN THE PATHOPHYSIOLOGY al., 2008). A group of pruritogens including infl ammatory lip- OF PRURITUS IN ATOPIC DERMATITIS ids, cytokines, neuropeptides, neurotransmitters such as his- tamine and serotonin (5-hydroxytryptamine, 5-HT), proteases, The skin of AD patients show infi ltrating CD11c+ dendritic proteinase-activating receptors, and opioid peptides appears cells and CD3+ T cells (Novak and Leung, 2011) mainly com- to be related to pruritus in AD (Darsow et al., 1997; Steinhoff posed of CD4+ and cutaneous lymphocyte associated antigen et al., 2006; Ständer et al., 2008; Lee, 2010). Among these (CLA)+ T cells (Leung and Bieber, 2003; Leung et al., 2004). factors, has been the most well-known pruritogen. The infi ltrates predominantly consist of interleukin 4 -produc- Histamine was found at high concentrations in AD lesions and ing Th2 type cells in the initial phase of AD, whereas chronic most of the cells involved in the infl ammatory responses ex- lesions frequently show infi ltrates with Th1 type (Leung and press the histamine 1 receptor (H1R) and histamine 2 receptor Bieber, 2003). It has been reported that Th2-type cytokines (H2R)(Mommert et al., 2011). There is a specifi c chemosensi- are involved in the interplay between nerves and T lympho- tive subpopulation of C-fi bers that mediate histamine-induced cytes indicating the roles of cytokines in pruritus (Sonkoly et pruritus (Schmelz, 2001; Schmelz et al., 2003). In this context, al., 2006; Cevikbas et al., 2011). However, a recent report H1R antagonists have been tried and demonstrated to reduce from biopsies taken from atopy patch test revealed that in ad- pruritus in numerous clinical trials (Sugimoto et al., 2004; Paus dition to CD4+ T cells, CD8+ T cells might play a pivotal role for et al., 2006). However, in AD patients, showed the development of eczema (Hennino et al., 2011). only limited clinical effi cacy to pruritus (Klein and Clark, 1999) Recently, a novel T cell-driven cytokine interleukin 31(IL- suggesting that histamine is unlikely to be a major peripheral 31) has been found to be signifi cantly upregulated in pru- mediator of pruritus in AD (Rukwied et al., 2000). ritic AD patients compared with healthy, nonatopic subjects Recently, the fourth (H4R) brought his- (Sonkoly et al., 2006). Actually IL-31 induced severe pruritus tamine back into focus in the pathophysiology of pruritus in and dermatitis in transgenic mice (Sonkoly et al., 2006). The AD. Several studies showed that the H4R, which is differen- sources of IL-31 include the activated skin infi ltrating CLA- tially expressed on immune and nonimmune cells, plays an positive T cells (Bilsborough et al., 2006). All these results important role in pruritus of AD patients (Dijkstra et al., 2007; back up the earlier reports suggesting that skin-infi ltrating T Gutzmer et al., 2009). Pruritus was selectively inhibited by the cells might play a major role in pruritus in AD (Wahlgren et al., treatment with a H4R antagonist in a Th2 cell-mediated mouse 1990; Greaves and Khalifa., 2004). skin infl ammation model that mimics several features of AD There is a specifi c type of T cells in the skin epidermis and (Cowden et al., 2010) or in H4R knockout mice (Dunford et intestinal epithelia, the γδ T cells. In contrast to the classical al., 2007). αβ T cells, γδ T cells have limited specifi cities of T cell recep- Despite of the newly discovered role of H4R in pruritus of tor (TCR), unusual dendritic shape, and functions distinct AD lesion, it is still accepted that histamine is not the sole from αβ T cells in many ways. These cells have been found mediator of pruritus in AD and mediators other than histamine to play crucial roles in tissue homeostasis and damage repair such as cytokines and neuropeptides may be involved in in- by recognition of damaged self (Jameson et al., 2002; Strid duction of intractable, recurrent pruritus in AD. This assump- et al., 2009), whereas αβ T cells function in foreign antigen tion is supported by the evidence of histamine-independent recognition. Epithelial γδ T cells express special costimulatory pruritus-specifi c fi bers in the skin (Nakano et al., 2008). molecules such as junctional adhesion molecule-like protein (JAML) (Witherden et al., 2010). Once activated, epithelial γδ T cells express cytokines that promote infl ammation and stim- ANTIPRURITIC EFFECTS OF IMMUNOMODULATING ulate repair of the skin tissue (Sharp et al., 2005). However, it THERAPY IN ATOPIC DERMATITIS is unknown what molecules are recognized by γδ T cells and by what mechanisms γδ T cells are activated. Controlling and treatment of chronic pruritus is one of the Interestingly, activation of H4R on Th2 cells increased the major unmet needs in the therapeutic approach to AD. Be- production of IL-31, which is one of important inducers of pru- cause of the multifactorial pathogenesis of AD, no specifi c, ritus in AD (Gutzmer et al., 2009), suggesting the possibility universally effective and well-tolerated antipruritic agent for AD that receptors of neuromediators might be involved in the acti- has been developed yet (Lee, 2010). Until now, management vation process of skin T cells. of pruritus in AD is mainly confi ned to imunomodulators such

507 www.biomolther.org Biomol Ther 20(6), 506-512 (2012)

INTERACTIONS BETWEEN NERVOUS SYSTEM AND ANTIPRURITIC EFFECTS OF PSYCHOTROPIC DRUGS IMMUNE SYSTEM IN ATOPIC DERMATITIS IN ATOPIC DERMATITIS AND THE ROLE OF 5-HT IN NEUROIMMUNE INTERACTION In the skin, the nervous and immune systems bidirectionally interplay via the action of neuromediators (neuropeptides and Another distinct feature of AD is the substantial infl uence of neurotransmitters) that are released by skin nerves and the psychological state on the intensity of pruritus. The majority immune cells (Luger, 2002; Straub, 2004). The cells of both of patients with AD reported that psychological stress aggra- systems are able to release neuromediators and respond to vated their pruritus, suggesting that pruritus might be closely them via specifi c receptors expressed on their surface. For related with emotional distress in AD (Wahlgren, 1992). In instance, skin immune cells such as mast cells and dendritic this context, various psychotropic drugs have been tried in cells release neuropeptides which induce activation of nerve clinic to relieve pruritus. However, only several psychotropic ending, vasodilatation, and plasma extravasation (Rooster- drugs showed real antipruritic effects in AD patients. Table 1 man et al., 2006). In turn, neuropeptides such as vasoactive summarizes the Ki (binding affi nity) values of the antipruritic intestinal peptide (VIP) and CGRP modulate the functions of psychotropic drugs to receptors and transporters for various macrophages and T cells (González-Rey et al., 2007) and neurotransmitters. The antagonist naltrex- langerhans cells (Cevikbas et al., 2007) respectively, while one showed antipruritic effect in patients with AD (Heyer and substance P affects lymphocyte proliferation and mast cell de- Hornstein, 1999). A showed granulation (Turner et al., 2007). Thus it seems quite reason- antipruritic effect topically and systemically for its additive an- able that neuromediators are involved in the pathogenesis of tihistaminic and anticholinergic effects (Drake and Millikan, pruritus in AD (Roosterman et al., 2006). Actually, stressed pa- 1995). trimipramine, that antagonizes tients with AD had increased numbers of 5-HT-receptive mast H1 receptor and H2 receptor, reduced nocturnal scratching in cells (Lonne-Rahm et al., 2008). patients with AD (Savin et al., 1979). Bupropion is an antide-

Table 1. Binding affi nities of antipruritic psychotropic drugs to receptors or transporters for various neuromediators

Ki (nM)

Cholinergic, Norepine- Name Mechanism Histamine Opioid Dopamin 5-HT 5-HT muscarinic phrine Trans- receptor 1 receptor receptor receotor 2 transporter receptor receptor transporter porter

Doxepin Tricyclic 0.24 23 α1: 23.5 29.5 >10,000 360 (brain) 68 1A: 276 anti- (brain) (brain) depressant α2: 1,270 2: 27 (brain) (brain)

Trimi- Tricyclic 1.4 (cortex) 2,450 3,780 149 pramine anti- depressant

Bupropion Atypical >10,000 >10,000 α1: 4,200 >10,000 541 >10,000 >10,000 1A : >10,000 anti- (cloned) (brain) (brain) (brain) depressant α2: >10,000 2 : >10,000 (brain) (brain)

Naltrexone Opioid δ: 26.6 receptor κ: 1.75 antagonist μ: 0.39

Paroxetine Selective >10,000 108 (brain) α1: 1,868 242 963 >10,000 0.58 1A : >10,000 serotonin (brain) (cortex) (brain) (brain) reuptake α2: 3,915 2 : >10,000 inhibitor (cortex) (brain)

Fluvox- Selective >10,000 α1: 1,288 2,931 >10,000 12.5 amine serotonin (cortex)

Ki values mean the binding affi nities of drugs to receptors and transporters for various neurotransmitters. Ki values used in this plot were adopted from PDSP Ki data base (http://pdsp.med.unc.edu/pdsp.php). ( ) means the source of receptor or transporter. Only the Ki values obtained using human source were identifi ed.

http://dx.doi.org/10.4062/biomolther.2012.20.6.506 508 Kim. Neuroimmunological Pruritus in Atopic Dermatitis

Fig. 1. Chemical structures of psychotropic drugs with antipruritic effects in patients of atopic dermatitis. pressant acting via inhibition of both noradrenaline and dopa- membrane-bound receptors, which are categorized into 7 mine reuptake. Case reports have shown that patients with families (5-HT1-7) with at least 21 subtypes (Mössner and AD can have symptomatic improvement with oral bupropion Lesch, 1998; Kroeze et al., 2002; Slominski et al., 2003). treatment (Gonzalez et al., 2006). Fig. 1 summarizes the Ki SERT determines the magnitude and duration of the sero- values of antipruritic psychotropic drugs to various receptors tonergic response via recycling released 5-HT in the synap- or transporters for neuromediators. tic cleft. Because SERT can terminate the action of 5-HT on In addition, psychotropic drugs that act on 5-HT receptor nerve, the SSRIs targeting SERT have been used as antide- or serotonin transporter (SERT) showed antipruritic effects in pressants and . AD. An 5-HT for 5-HT1A receptor, tando- However, 5-HT receptors and SERT are not confi ned to spirone citrate showed a signifi cant improvement in SCORAD nerves. 5-HT receptors were found to be expressed on lym- (SCORing Atopic Dermatitis) indices (Kawana et al., 2010). phocytes, dendritic cells and macrophages (Meredith et al., The selective serotonin reuptake inhibitor (SSRI) paroxetine 2005). Expression of SERT on human blood lymphocytes and fl uvoxamine considerably reduced pruritus in patients (Faraj et al., 1994), murine peritoneal macrophages and den- with AD in an open label two-armed proof of concept study dritic cells (Rudd et al., 2005) has been reported. (Diehn and Tefferi, 2001; Ständer et al., 2009). Yaris et al. In human skin, Slominski et al. reported an expression of and Zylicz et al. suggested that antipruritic effect of paroxetine the serotonergic receptors on human keratinocytes, melano- might be predominantly due to its central action rather than cytes and dermal fi broblasts (Slominski et al., 2003). 5-HT1A peripheral effects (Yaris et al., 2003; Zylicz et al., 2003). How- receptors were found on mast cells and melanocyte-like cells, ever, considering the reports that intradermal administration 5-HT2A receptors and SERT on lymphocytes, NK cells and of 5-HT could induce pruritus (Yamaguchi et al., 1999) and langerhans cells (LCs) in the eczematous skin of patients suf- that selective 5-HT1A receptor agonist, tandospirone citrate fering allergic contact dermatitis (El-Nour et al., 2007). Phar- inhibited stress-enhanced degranulation of skin mast cells macological studies indicate that 5-HT3 receptors are also (Shimoda et al., 2010), further studies should be conducted to expressed on sensory nerve endings (Weisshaar et al., 1997). elucidate whether the antipruritic effects of these serotonergic CD3+ cells in skin co-expressed 5-HT2A and SERT (El-Nour drugs are due to the central sedative effect based on their et al., 2007). Moreover, skin mast cells showed increased additive antihistaminic or anticholinergic action or peripheral expression of serotonin receptor 5-HT1A, 5-HT2A, SERT in effect. 5-HT is one of the key neurotransmitter that acts in lesional skin of patients with stress-associated AD, compared both central and peripheral nervous system (Slominski et al., with non-lesional skin (Lonne-Rahm et al., 2008). Fig. 2 sum- 2005). Dysregulation of 5-HT leads to sleep disorder, , marizes the reports about the role of serotonin in neuroimmu- depression, and aggressiveness. In vitro results show that nologicalinteraction in skin of atopic dermatitis patients. 5-HT exerts variable effects on skin cells (Slominski et al., A recent paper suggested a possible association between 2003). It stimulates growth of dermal fi broblasts in a dose- polymorphisms in the SERT gene and aggravation of AD. dependent manner (Seuwen and Pouyssegur, 1990). Immor- Among the three known polymorphisms affecting transcrip- talized epidermal melanocytes exhibit serotonin-stimulated tion of SERT gene, a tendency towards high prevalence of the growth when the cells had been cultured without melanocyte short (10-copy) variant of STin2 was found in AD patients. All growth supplements (Slominski et al., 2003). In addition, re- AD patients with high-anxiety traits carried the short variant of cent reports showed that 5-HT induces melanogenesis via STin2. In the corresponding healthy control group, the preva- 5-HT receptor 2A(5-HT2A)(Lee et al., 2011). lences of the 10-and 12-copy variants were 62% and 38%, re- In skin, 5-HT is involved in vasodilaion, infl ammation, im- spectively (p<0.01) (de Mel et al., 2012). Interestingly, 5-HT is munomodulation and pruritogenic effects via interaction with also reported to modulate T-cell activation and differentiation

509 www.biomolther.org Biomol Ther 20(6), 506-512 (2012)

Fig. 2. Graphic summary about the role of serotonin in neuroimmunological interaction in skin of atopic dermatitis patients.

strongly suggesting 5-HT as one of key mediators in signal- SUMMARY ling between nervous system and immune system (Aune et al., 1993; Aune et al., 1994; Gordon and Barnes, 2003). Thus Controlling and management of prurirtus still remains as it is not surprising that serotonergic drugs showed modulat- unmet needs mainly due to the distinctive multifactorial patho- ing effect on cells of the immune system (Frank et al., 1999; genesis of pruritus in AD. Based on the distinct feature of AD Pellegrino and Bayer, 2000). Release of 5-HT by fenfl uramine that psychological state of patients substantially infl uence the treatment has been shown to decrease whole blood lympho- intensity of pruritus, various psychotropic drugs have been cyte proliferation in rats (Connor et al., 2000). In addition, a used in clinic to relieve pruritus of AD patients. Only several SSRI fl uoxetine and 5-HT2 receptor agonist 2, 5-dimethoxy- psychotropic drugs including SSRI were reported to show real 4-iodoamphetamine (DOI) administration resulted in a signifi - antipruritic effects in AD patients and the precise mechanisms cant decrease in concanavalin A-induced lymphocyte prolifer- of antipruritic effect of these drugs are still unclear. Interesting- ation (Pellegrino and Bayer, 2002). Pellegrino et al. suggested ly, drugs that increased 5-HT concentration showed signifi cant the effects of fl uoxetine on lymphocyte proliferation were the decrease in lymphocyte proliferation, suggesting that antipru- result of elevated central serotonin neurotransmission and ritic effects of SSRIs in AD patients might at least partly due activation of central 5-HT2 receptors, because pretreatment to their suppressive effect on T cells considering the critical with the 5-HT2 antagonist or almost com- roles of skin T cells in the pathophysiology of atopic dermatitis. pletely antagonized the decrease in lymphocyte proliferation However, further studies should be conducted to elucidate the by fl uoxetine (Pellegrino and Bayer, 2002). On the other hand, precise mechanism of neuro-immune interaction in pruritus of a couple of reports showed that fl uoxetine promoted the Ca2+- AD. mediated proteolysis of protein kinase C and increased cyclic AMP levels, impairing proliferation of human peripheral blood T cells, when optimal mitogenic stimuli was used (Edgar et ACKNOWLEDGMENTS al., 1999). CD3+ cells in skin co-expressed 5-HT2A and SERT (El-Nour et al., 2007). Thus the question whether the cyclic The present research was conducted by the research fund AMP-mediated suppression of T cell proliferations by fl uox- of Dankook University in 2011. etine might work in skin T cells and by other SSRI needs fur- ther study. Considering all these results and the critical roles of skin T REFERENCES cells in the pathophysiology of AD, the antipruritic effects of SSRIs in AD patients might be due to their suppressive effect Andrew, D. and Craig, A. D. (2001) Spinothalamic lamina I neurons on T cells at least partly. However, it is still unclear whether the selectively sensitive to histamine: a central neural pathway for itch. antipruritic effects of neuromodulators are mediated directly Nat. Neurosci. 4, 72-77. Aune, T. M., McGrath, K. M., Sarr, T., Bombara, M. P. and Kelley, K. via suppression of lymphocyte function or indirectly by the A. (1993) Expression of 5HT1a receptors on activated human T modulation of neuro-immune interaction. http://dx.doi.org/10.4062/biomolther.2012.20.6.506 510 Kim. Neuroimmunological Pruritus in Atopic Dermatitis

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