from the brain-skin connection: the neuroendocrine-immune misalliance of stress and itch

Fax +41 61 306 12 34E-Mail [email protected]

Neuroimmunomodulation 2006;13:347–356

DOI: 10.1159/000104863

From the Brain-Skin Connection: The Neuroendocrine-Immune Misalliance of Stress and Itch

Petra Arck a Ralf Paus b

a Center for Internal Medicine and Dermatology, Charité, University Medicine Berlin, Berlin , and

b Department of Dermatology, University Hospital Schleswig-Holstein, University of Lübeck, Lübeck , Germany

ic skin inflammation and itch as a neuroendocrine-immune

‘misalliance’. We argue that key candidate molecules of the

stress response with strong pruritogenic potential, such as

nerve growth factor, corticotropin-releasing hormone and

substance P, and mast cells, which may be considered as

‘central cellular switchboards of pruritogenic inflammation’,

need to be further explored systematically in order to de-

velop more effective therapeutic combination strategies for

itch management in chronic, stress-vulnerable inflammato-

ry skin diseases Copyright © 2006 S. Karger AG, Basel

Key Protagonists of the Stress Response

The human organism is normally in a state of a dy-namic equilibrium. Perceived stress has long been allied with disturbances of this equilibrium, leading to chronic hyperarousal and/or hyporesponsiveness, which in turn exacerbate disease manifestation [1–4] . It is generally ac-cepted that neural and neuroendocrine processes coordi-nate and regulate adaptation processes in response to stress. These typically include behavioral, cardiovascu-lar, metabolic, endocrine and immunological changes

Key Words

Stress � Pruritus � Neurogenic inflammation � Mast cells �

Skin � Immunodermatoses

Abstract

Perceived stress has long been allied with disturbances of

the dynamic equilibrium established between the nervous,

endocrine and immune systems, thus triggering or aggra-

vating disease manifestation. Several common skin diseases

are now acknowledged to be worsened by psychological

stress, particularly immunodermatoses such as atopic der-

matitis, psoriasis, seborrheic eczema, prurigo nodularis, li-

chen planus, chronic urticaria, alopecia areata and pruritus

sine materia. Itch (pruritus) is perhaps the most common

symptom associated with a majority of these inflammatory

skin diseases, and acute as well as chronic stress perceptions

are recognized to trigger or enhance pruritus. A wealth of

mediators released systemically or locally in the skin in re-

sponse to stress increase sensory innervation, upregulate

the production of other pruritogenic agents, perpetuate

(neurogenic) inflammation and lower the itch threshold. In

the present review, we explore recent frontiers in both stress

and pruritus research and portray the perpetuation of chron-

Published online: August 6, 2007

Petra Arck, MD AG PsychoNeuroImmunologie, Med. Klinik mit Schwerpunkt Psychosomatik Charité, Campus Virchow, Forum 4, Raum 2.0549 Augustenburger Platz 1, DE–13353 Berlin (Germany) Tel. +49 30 450 553 873, Fax +49 30 450 553 962, E-Mail [email protected]

© 2006 S. Karger AG, Basel 1021–7401/06/0136–0347$23.50/0

Accessible online at: www.karger.com/nim

Arck /Paus

Neuroimmunomodulation 2006;13:347–356 348

[1–7] . In this context, the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic and parasympathetic system are key adaptation responses to stress, which subsequently interfere with immune re-sponses [4, 7–9] . These (both genetically determined and learned) stress responses play an important role in deter-mining an individual’s relative susceptibility and resis-tance, e.g. to inflammatory and infectious diseases ( ta-ble 1 ) [4, 10, 11] .

Besides classical stress-related neurohormones like the players of the HPA axis – corticotropin-releasing hor-mone (CRH), adrenocorticotropic hormone, prolactin and glucocorticoids – the neurotrophin nerve growth fac-tor (NGF) is now recognized as a crucial mediator of stress responses [12–14] . Recent findings indicate that circulat-ing levels of NGF undergo significant variations after ex-posure to stressful events [12, 13] . Besides its function as an important trophic factor for neuropeptidergic and sympathetic neurons, NGF is now increasingly accepted as a potent immunomodulator, promoting ‘cross-talk’ be-tween neuronal and immune cells ( table 1 ) [15] .

The neuropeptide substance P (SP) is another major mediator of the systemic stress response. Since von Euler and Gaddum [16] first described SP more than 70 years ago, much evidence has accumulated to suggest that this undecapeptide can indeed be considered as the prototyp-ic stress-related neuropeptide, which inevitably induces an immune response towards inflammation ( table 1 ) [17–19] . The central role of SP in the neuroimmune context is further supported by recent studies reporting a reduced response to pain or stress and subsequent lack of inflam-mation in mice upon genetical disruption of the SP pre-cursor preprotachykinin A or of the neurokinin-1 recep-tor, for which SP has the highest affinity [20, 21] .

Clearly, the long-dominant paradigm of stress-in-duced immunosuppression as the sole effect of stress on the immune system has been challenged over the past decade and replaced by a more complex, differentiated concept of how stress impacts on the immune system [9, 22, 23] . It is now generally accepted that the activation of the sympathetic nervous system and the release of NGF and SP during stress response trigger an intense inflam-matory response, e.g. in the skin in the setting of chronic diseases such as rheumatoid arthritis, whereas a systemic inflammatory response generally is suppressed ( table 1 ) [6, 10, 13, 17, 24] . Stress-triggered inflammatory events in peripheral tissues predominately affect the epithelium [4] and mast cells play a pivotal role as central switchboards of stress adaptation pathways in the periphery ( fig. 1 , see below) [17, 23, 25–30] .

Increasingly more mechanisms are identified where the central nervous system (CNS), the neuroendocrine system and the immune system interact through neuro-nal pathways, hormonal cascades and interactions of the immune system on a cell-to-cell basis or as sentinel organ for neuroendocrine stress mediators [2, 4, 6, 7] . Vice ver-sa, the peripheral immune system may also regulate the CNS [31] . Cytokines are important partners in this cross talk, modulating the HPA axis responses at all 3 levels: the hypothalamus, the pituitary gland and the adrenals [31] . During inflammation, cytokines secreted from in-flamed peripheral epithelial tissue sites, such as the intes-tinal mucosa, can signal to the brain and may subse-quently influence behavior and other complex body reac-tions, commonly referred to as sickness behavior [31, 32] . Immunological events in the periphery may even affect certain brain areas to induce depression-like behavior. For example, immune cells – activated in response to in-fection, inflammation, trauma or stress – release proin-flammatory cytokines, which in turn signal to the CNS and create exaggerated pain perception and/or induce physiological, behavioral and hormonal changes [31, 32] . These changes, accompanied by the release of proinflam-matory cytokines by glia within the brain and spinal cord, are termed sickness response [32] . Regions of inter-est in the brain directly or indirectly involve structures associated with the central stress system, in particular the hypothalamus, hippocampus, frontal/prefrontal struc-tures and the limbic system including the amygdala [32] . Hence, besides psychosocial stress (e.g. induced by exter-nal demands or situational stress), the stress system can clearly be activated by various endogenous inflammatory stimuli arising from the periphery, such as the skin.

Stress and the Skin

The skin is the largest organ of the body and plays a pivotal role in host defense. The primary function of the epidermis is to protect, i.e. to prevent desiccation and to serve as a barrier to physical, chemical and biological threats in the environment [15] . However, over the past two decades, the integument has also become appreciated as an astoundingly active (neuro)endocrine and immu-nomodulatory organ, which displays its own fast-re-sponse systems to both oxidative and psychoemotional stress [14, 15, 33–35] . The ‘excitability’ of one of our key organs by stressful stimuli and the alteration of bodily functions by psychological stress is nowhere more instan-taneously evident to the naked eye than in the skin. Here,

The Neuroendocrine-Immune Misalliance of Stress and Itch


Mediator Effect on immune response Skin target cells Releasedin stressresponse

Prurito-genicactivity

Role in pruritussignaling

Selectedrefer-ences

Catechol-amines

–

–

–

––

Regulate the immune system at regional, local andsystemic levels via adrenergic receptors expressedon immune cellsElectively suppress cellular immunity and enhancehumoral immunity (�2-adrenergic receptors areexpressed on Th1 cells, but not on Th2 cellsInduce lymphocytosis, affect lymphocyte traffic,circulation, and proliferationModulate cytokine production Stimulate or augment mast cell activation

Keratinocytes,lymphocytes,melanocytes,dermal fibroblasts, EC

+ + Mediate itchin AD patients

[6, 7, 40]

Hemokinin ––

Activates mast cellsInduces vascular permeability

Mast cells, EC + No effects reported yet

[15, 42]

CGRP –

––

Inhibits proliferation and IL-2 release of T lymphocytes under immune challengesActivates mast cellsInduces vascular permeability

Mast cells,immunocytes

+ + Sensitization of nerveendings, involved initchy skin diseases

[15]

Cytokines – Induce apoptosis, proliferation, immunity, tolerance Leukocytes,keratinocytes,EC, nerves

+ + Release of IL-31 byT cells during inflammation, IL-31 is upregulatedin AD and pruritus

[6, 7, 9, 23, 26]

�-Endorphin ––

Affects chemotaxis and phagocytosis of macrophagesInteracts with mast cells

Mast cells,macrophages

+ + Increased �-endorphin serum levels in children with AD and pruritus

[15]

Endothelin – Affects tissue perfusion, leukocyte extravasation and immune cell function

Endothelium,mast cells

+ + Mediates burning itch, degraded by mastcell-derived chymase

[27]

Endo-vanilloids

––

–

Deplete neuropeptides from sensory neuronsAffect proliferation, differentiation, apoptosis andcytokine releaseInhibitors of early and late events in TCR-mediatedT cell activation

Sensory neurons,mast cells,keratinocytes,Langerhans cells,sebocytes

No effects reportedyet

+ Increased expression in keratinocytes in prurigo nodularis

[45]

Histamine –––

–

H1 receptor promotes allergic inflammatory reactionsH1 receptor augments Th1 responsesH2 receptor suppresses Th responses, participation in immune tolerance via IL-10 and TGF-�H4 receptor affects hematopoietic system

Sensory nerve fibers

+ + Induces itch by stimulating specific sensory fibers in humans

[15, 40, 50–52]

Hormonesof the HPAaxis (CRH,ACTH, GC)

–––

–

Activate mast cellsUpregulate production of IL-4, IL-6, IL-10 and IL-13 Inhibit the production of IL-12, IFN-� and TNF-�by APC and Th1 cellsRelevant examples of proinflammatory actions ofCRH have been introduced

CRH-R1expressed onkeratinocytesand mast cells

+ + Release of histamine,cytokines, TNF,VEGF from mast cells

[2, 3, 5, 8]

Kallikreins,proteases

––

–

Promote vascular permeability Tissue remodeling through selective proteolysis of matrix proteins Recruitment of inflammatory cells

Keratinocytes,EC, mast cells,platelets

+ + Massive scratching in mice overexpressing kallikrein-7,chymase degradespruritic and antipruritic peptides, tryptase induces inflammation and itch via PAR2

[15]

Table 1. Common denominators of the stress response and itch (pruritus)

Arck /Paus


excessive sweating (hyperhidrosis) and ‘flushing’ (facial erythema) can be worsened by psychoemotional stress. In addition, chronic inflammatory skin diseases such as atopic dermatitis, psoriasis, seborrheic eczema, prurigo nodularis, lichen planus, chronic urticaria, alopecia area-ta and pruritus sine materia have long been recognized by clinicians to deteriorate in response to psychological stress [14, 15, 35, 36] .

Psoriasis is a classical example of a chronic inflamma-tory, hyperproliferative skin disease whose course dete-

riorates or whose relapses are triggered in response to psychological stress [36] . It was originally speculated that the neuropeptide SP, which is released in response to stress by sensory, peptidergic skin nerves, is the main me-diator in psoriasis [37] . Interactions between nerves, neu-ropeptides and mast cells, leading to neurogenic inflam-mation, have also been implicated in another frequent chronic immunodermatosis, atopic dermatitis [38] . In fact, recent work on a mouse model of stress-induced neurogenic skin inflammation, has provided a concep-

Table 1 (continued)

Mediator Effect on immune response Skin target cells Releasedin stressresponse

Prurito-genicactivity

Role in pruritussignaling

Selectedrefer-ences

Leuko-triene B4

–

–

Chemoattractant for myeloid and cytotoxic effectorT cellsRegulating pathologic inflammation

Sensory nerve fibers,keratinocytes

+ + Induces itch and is involved in the SP-mediatedinduction of itch

[15]

NGF –––

–

–

Activates mast cellsInduces vascular permeabilityPromotes ‘cross-talk’ between neuronal and immune cellsActs as autocrine and paracrine factor in the development and regulation of immune cells Promotes monocyte/macrophage migration throughvascular endothelium

Keratinocytes,mast cells,fibroblasts,eosinophils

+ + NGF levels enhanced in AD, induces tryptase release from mast cells

[12, 13, 33, 39]

NPY ––

Activates mast cells Induces adherence, chemotaxis, phagocytosis,lymphoproliferation, antibody and cytokine production

Mast cells,immunocytes

+ No effects reported yet

[15]

PACAP – Activates mast cells, induces vascular permeability Mast cells, EC + No effects reported yet

[15, 29]

PRL ––

–

Participates in early and late T cell-activating eventsContributes to a proinflammatory andapoptosis-prone environmentImmune-competent cells contain PRL mRNA and release a bioactive PRL which is similar to pituitary PRL

Epithelium ofhuman anagenhair follicles


[15]

SP –––

Induces inflammation Induces lymphocyte proliferation Primes mast cells to release of TNF, histamine,leukotriene B4, prostaglandins

Sensory nerve fibers

+ + Induces intense itch in lesional skin of AD patients; possibly key mediator of itching in AD

[14–19]

SCF ––

Promotes mast cell proliferation and migrationActivates mast cells


[41]

ACTH = Adrenocorticotropic hormone; AD = atopic dermatitis;APC = antigen-presenting cells; CGRP = calcitonin gene-related peptide; CRH = corticotropin-releasing hormone; CRH-R = corticotropin-releas-ing hormone receptor; EC = endothelial cells; GC = glucocorticoids; IFN = interferon; IL = interleukin; NGF = nerve growth factor; NPY = neuropep-

tide Y; PACAP = pituitary adenylate cyclase-activating polypeptide;PAR2 = proteinase-activated receptor 2; PRL = prolactin; SCF = stem cell factor; SP = substance P; TCR = T cell receptor; TGF = transforming growth factor; Th = T helper; VEGF = vascular endothelial growth factor; TNF = tumor necrosis factor; mRNA = messenger RNA.



Triggers of mast cell activation

Hormones (CRH, ACTH)

Cytokines (IL-1, IL-2, TNF-�)

Growth factors (NGF, SCF)

Neuropeptides (SP, CGRP, VIP)

Hemokinin A

Neurotensin

PACAP

New synthesis of mediators,

released upon degranulation

IL-1, IL-2, IL-3, IL-4,

IL-5, IL-6, IL-10, IL-13,

IFN-�, TNF-�

Chemokines

VEGF, leukotriene, prostaglandin

Nitric oxide

NGF, TGF-�

Release of prestored mediators

Tryptase, chymase

TGF-�, GM-CSF, NGF

SP, VIP, CRH

Histamine

Heparin

a b

d

e f

MC

N

c

V

MC

EG

Fig. 1. Skin mast cells as stress sentinels and effector cells in the neuroendocrine-immune environment. a Trig-gers of mast cell activation. b – d Photomicrographs of murine skin. b The spatial close contact of mast cells (appearing in fluorescence green) and SP-positive nerve fibers (red-labeled delicate fiber) is increasingly detect-able in response to stress. c Mast cells can frequently be identified near blood vessels in the subcutis of murine skin. Activated (i.e. degranulated) mast cells can be identified by the presence of extracellular granules. d The close contact of mast cells and nerve fibers can be confirmed by electron microscopy. e Mediators which may be newly synthesized by mast cells and released upon degranulation. f Mediators which are prestored in mast cells and may be released upon degranulation. ACTH = Adrenocorticotropic hormone; CGRP = calcitonin gene-related peptide; EG = extracellular granules; GM-CSF = granulocyte macrophage colony-stimulating fac-tor; IFN = interferon; IL = interleukin; MC = mast cells; PACAP = pituitary adenylate cyclase-activating poly-peptide; SCF = stem cell factor; TGF = transforming growth factor; TNF = tumor necrosis factor; V = blood vessels; VEGF = vascular endothelial growth factor; VIP = vasoactive intestinal polypeptide.

Arck /Paus


tual tapestry for the general principles along which stress is likely to modulate the skin immune system in these diseases via upregulation of NGF and SP [13, 17] .

Evidently, the skin is the most accessible organ system for investigating the peripheral effects and production of key stress mediators, and subsequently, insights into neu-roendocrine-immune dysregulations that may underlie the provocation or aggravation of immunodermatoses by stress have become increasingly available in recent years [14, 15, 35] . This may be explained by the fact that the in-cidence of some of these skin diseases, like atopic derma-titis, seems to have significantly increased over the past decades, thus moving them closer to the center of bio-medical research interests. Also, the – often dramatic – decline in the quality of life of affected individuals that is caused by stress-modulated immunodermatoses has des-ignated these skin conditions model diseases for interdis-ciplinary research endeavors.

In-depth systematic scientific exploration of the so-called ‘brain-skin connection’ [15] is relatively easy since skin response patterns to stress are easily discerned and measured, and tissue sampling for detailed analysis of mechanisms and mediators is relatively unproblematic. From the growing scientific attention that the brain-skin connection has received over the past decade, we now know that – due to the common neuroectodermal origin of the skin with the CNS, which is reflected by the skin’s unusually dense and intricate innervation – numerous neurotransmitters, neuropeptides, neurotrophins and neurohormones are present locally and act both as major targets and effector messengers of the stress response [14, 15, 38, 39] . In fact, essentially all of the key players of neu-roendocrine-immune signaling in response to stress, as listed in table 1 , have now been identified to be generated by cutaneous cell populations as well.

Mast Cells as Neuroendocrine-Immune

Switchboards during Stress Responses

In keeping with their recently established role as key protagonists of innate epithelial immunity, and based on their prominent association with blood vessels ( fig. 1 c), peripheral nerve fibers ( fig. 1 b, d) and hair follicles [13, 15, 27] , mast cells serve as crucial sentinels in host de-fense. Thus, mast cells have moved on from serving as ‘central switchboards of neurogenic inflammation’ [28] to operating as infinitely more complex multipurpose interface regulators which join, at the tissue level, the nervous, endocrine and immune systems [15, 23, 25, 27,

29, 30] . Thus, mast cells compute activation signals re-ceived via both systemic and locally generated neuroen-docrine stress messengers such as CRH, NGF, SP and others ( fig. 1 a). Upon activation, mast cells then release a multitude of prestored or newly synthesized factors ( fig. 1 e, f). The close level of mast cell integration into neuroendocrine-immune networks is probably most easily examined and best documented in the skin, and here again is particularly prominent during pruritus [15, 40] .

The pivotal role of mast cells as switchboards for stress responses that lead to skin inflammation is illustrated for example by mast cell degranulation in response to acute stress or administration of CRH, the most proximal ele-ment of the central HPA stress response axis, both in vivo and in vitro [25] . Also, CRH administration induces neu-rogenic inflammation in rat skin, and CRH-neutralizing antibodies abrogate stress-induced degranulation of skin mast cells [23] . NGF – the key growth factor released dur-ing systemic stress responses [12, 13] – promotes mast cell maturation, survival, proliferation and degranulation [27] . Further, stress-induced upregulation of SP results in activation/degranulation of skin mast cells [17] via the high-affinity SP receptor neurokinin-1 [17, 21] , which may be upregulated by interleukin-4 or stem cell factor [41] . In a murine model of acoustic stress, NGF (which stimulates SP synthesis in sensory neurons) appeared to function as dominant regulatory element proximal of this SP-induced activation of skin mast cells [13] . In ad-dition, IgE, antigens, free immunoglobulin light chains, anaphylatoxins, cytokines, hormones, endovanilloids and neuropeptides all can trigger mast cell secretion [18, 29] . Besides NGF and SP, the latter include neurotensin, hemokinin A and pituitary adenylate cyclase-activating polypeptide, all of which reportedly are upregulated dur-ing stress responses [15, 18, 29, 30, 42] .

Upon activation, mast cells secrete a multitude of va-sodilatory and proinflammatory mediators, such as his-tamine, heparin, kinins, proteases (preformed) and leu-kotrienes, prostaglandins, nitric oxide and cytokines (newly synthesized). In addition to histamine, vasoactive intestinal polypeptide and tumor necrosis factor (TNF), mast cells also release vascular endothelial growth factor, an isoform of which is particularly vasodilatory [15, 23, 26] . Moreover, overexpression of vascular endothelial growth factor in mouse skin causes a psoriasiform skin inflammation, and mast cells may be involved in promot-ing the cascade of intracutaneous events that leads to pso-riasis [15, 23, 24] .



Mast cells can undergo ultrastructural alterations of their electron-dense granular core indicative of secre-tion, but without degranulation – a process termed ‘in-tragranular activation’ [26] . Such activation may be as-sociated with the ability of mast cells to selectively re-lease key mediators of skin inflammation, as reported for example for serotonin, interleukin-6 and TNF [26] . Mast cell-derived TNF enhances T cell activation [15] , and mast cell-derived proteases activate proteinase-ac-tivated receptors (PAR) [43] on sensory neurons, which in turn augment the inflammatory response via the re-lease of additional SP [44] . Since tryptase-releasing mast cells are found in close proximity to PAR2-expressing cells, such as keratinocytes, dermal endothelial cells and C-fibers during inflammation [44] , positive feedback loops centering on the mast cell can be envisioned by which stress-induced and/or neurogenic inflammation is rapidly upregulated. The regulation of PAR2 expres-sion by stress remains to be elucidated; however, in-creased tryptase expression in murine skin in response to stress has recently been observed [Arck and Paus, un-published observation], suggesting that stress percep-tion may at least indirectly activate PAR2 expression via tryptase in the skin.

Stress and Itch: A Neuroendocrine-Immune

Misalliance?

Itch (pruritus) is perhaps the most common symptom associated with numerous inflammatory skin diseases and intriguingly, it has long been recognized that acute as

well as chronic stress perception triggers or enhances pru-ritus [35, 40] . Even though the neurophysiology of itch is surprisingly complex, abounding in unanswered ques-tions and often still speculative conflicting concepts, in recent years, we have begun to slowly acquire a better un-derstanding of shared pathways, mediators, cellular pro-tagonists and regulatory principles employed in both the stress response and the pathogenesis of itch [15, 45–47] .

Pruritogenic pruritus, which arises from skin diseases [40, 45, 48] , is the most frequent type of pruritus and re-quires the participation and activity of cutaneous sen-sory neurons that transmit the ‘itch’ signals via dorsal root ganglia and the spinal cord to the CNS. It has been known for decades that acute or chronic skin inflamma-tion lowers the threshold for pruritic stimuli and thus causes peripheral itch sensitization [48, 49] .

Several novel, and possibly not yet broadly enough ap-preciated, key messengers of pruritus or itch-relevant re-ceptors, such as proteases, leukotrienes, ion channels and cytokines, have recently been described, most of which are released within the stress response ( table 1 ). Notably, the role of histamine as the central messenger of itch may have been overrated in the past, since the efficacy of non-sedative antagonists of the histamine receptors H1 and/or H2 has been controversially discussed [50, 51] . None-theless, additional histamine receptors have been discov-ered and at least one of them (H4) operates as an ‘itch receptor’ in mice [52] . This finding sheds new light on this old itch suspect and may explain why H1 receptor antagonists are not efficient in certain pruritic skin dis-eases. Nonetheless, histamine as well as other prurito-gens such as pH changes, opioids, proteases, cytokines,

Release of

mediators

aggravation

threshold and

scratching

Stress response

execution

Perpetuation

of stress perception

Central stress response Skin stress response

Lowered itch

stress response

Incidence/

of chronic

skin diseases

Fig. 2. The neuroendocrine-immune loop of stress and itch. Upon stress exposure, the central stress responses comprises the acti-vation of the HPA axis, the sympathetic nervous system, which triggers a skin re-sponse to stress, reflected by the release of elements of stress response execution such as NGF, SP and mast cell activation, inevi-tably aggravating chronic skin diseases. This inflammatory skin environment low-ers the threshold for pruritic stimuli and thus causes peripheral itch sensitization. Cutaneous sensory neurons transmit the ‘itchy’ signals via dorsal root ganglia and the spinal cord to the CNS, and in turn per-petuate stress perception. Itch-provoked scratching enhances this vicious cycle by causing supplementary skin inflammation.

Arck /Paus


acetylcholine and neurotrophins, which may be more powerful itch inducers than histamine, may be released within the stress response [6, 12, 13, 21, 23, 46] . Subse-quently, intracutaneous inflammation and the vicious cycles of neurogenic inflammation in chronic skin dis-eases may be perpetuated, which provides insights into how stress perception also enhances pruritus ( fig. 2 ) [14, 40] .

Further, the ‘stress messenger’ NGF is thought to be involved in the pathogenesis of pruritic dermatoses such as prurigo nodularis and atopic dermatitis [38, 53] . A sig-nificant upregulation of intracutaneous NGF production in response to stress, accompanied by the increased ex-pression of cognate receptors by inflammatory stimuli (e.g. in the context of atopic dermatitis) may increase sen-sory innervation, amplify the expression and/or sensiti-zation of other receptor systems involved in itch patho-genesis (e.g. vanilloid receptors), upregulate the produc-tion of other pruritogenic agents such as SP, perpetuate inflammation and ultimately lower the itch threshold [13, 17, 40, 48] . Scratching activity of affected individuals fur-ther contributes to the perpetuation of skin inflamma-tion and causes additional stress [45] .

PAR2, activated by tryptase during inflammation, is also involved in the mediation of neurogenic inflamma-tion [43] and PAR2 agonists induce pruritus in these atopic dermatitis patients, suggesting that PAR2 – similar to histamine receptors – is a receptor for ‘itchy’ proteases [43] . Tryptase and PAR2 are upregulated on sensory nerves (e.g. during atopic dermatitis) and – as shown to date for tryptase – in response to stress [ 44 ; Arck and Paus, unpublished observation], suggesting that trypt-ase/PAR2 are crucial messengers in stress adaptation processes associated with increased pruritus.

Recent findings shed new light on the role of chronic inflammatory stimuli in pruritus with special attention to central sensitization of itch fibers. Activity in pruricep-tors not only provokes itch but additionally facilitates spi-nal itch processing, resulting in touch- or brush-evoked pruritus around an itching site (itchy skin) [40] . It re-quires ongoing activity in primary afferents and is most probably elicited by low-threshold mechanoreceptors (A- � fibers) [45, 46] . Moreover, even normally painful stim-uli can be misinterpreted as itch in a chronic itch con-dition when applied directly to pruritic skin lesionsand ongoing activity of pruriceptors, which presumab - ly underlies central sensitization for itch, has alreadybeen confirmed microneurographically in patients with chronic pruritus [49] . Thus, there is emerging evidence for a role of central sensitization in itch modulation dur-

ing chronic pruritus and future research must reveal if this central itch sensitization is perpetuated in response to stress.

Conclusion and Perspectives

This excursion to some recent frontiers in pruritus as well as stress research has demonstrated that shared path-ways and common mediators are involved in perpetuat-ing chronic skin inflammation and lowering the itch threshold ( fig. 2 ). Clearly, despite the complexity of inter-actions between the central and peripheral nervous sys-tem and the skin in response to stress, a broad spectrum of specific, well-defined molecular targets of stress-trig-gered pruritus has moved into view and now invites phar-macological targeting.

If these ‘common denominator’ molecules of stress ad-aptation and itch (such as NGF, CRH, SP and their cog-nate receptors) are further explored systematically, the development of more effective therapeutic combination strategies for pruritus management in chronic skin dis-eases may soon become available. The impressive efficacy of systemically administered agents that, for example, an-tagonize the proinflammatory activities of the key stress mediators CRH, NGF and SP in murine or rat skin [13, 17, 25] holds out a strong promise for clinical medicine that the notorious neuroendocrine-immune ‘misalliance’ between stress and itch that ruins the quality of life of uncounted patients, at long last, can be disrupted.

Acknowledgments

Aspects of our own work cited herein were made possible by grants provided by the German Research Foundation to R.P. (Pa 345/11-2) and P.A. (Ar 232/14-2). We thank B. Handjiski, A. Peter, E. Hagen and D. Tobin for their support in generating the photo-micrographs displayed in figure 1 .

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from the brain-skin connection: the neuroendocrine-immune misalliance of stress and itch

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