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Clinic Rev Allerg Immunol (2011) 41:259–266

DOI 10.1007/s12016-010-8225-z

Atopic Dermatitis and the Nervous System
Laurent Misery

Published online: 23 December 2010
# Springer Science+Business Media, LLC 2010

Abstract Due to the narrow associations between the skin, eruptions. This role was sometimes called into question until
immune system, and nervous system, nerve endings are the 1990s [1] because it was poorly understood. However,
very important in the pathophysiology of inflammatory new data clearly demonstrate that nerve cells are dramati-
dermatoses and especially in atopic dermatitis. Many cally involved in the pathophysiology of atopic dermatitis.
neurotransmitters and nerve growth factors that are released The term “neurodermitis”, which is often used in German to
in blood or skin are involved in neurogenic inflammation, denote “atopic dermatitis”, appears to be appropriate.
which dramatically enhance the inflammation induced by
immune cells. During times of stress, their release is highly
enhanced. In atopic dermatitis lesions, there are many The Neuro–Endocrino–Immuno–Cutaneous System
specific changes in skin neurobiology and neurophysiology.
These interesting data suggest that novel therapeutic The skin’s innervation is very dense. Nerve fibers innervate
possibilities can be imagined. the skin within the hypodermis, dermis, and epidermis up to
the outermost epidermal layers. In the skin, neurons can
Keywords Atopic dermatitis . Skin . Nerve . Neuropeptide . have anatomical contacts with all types of cutaneous cells
Neurotransmitter . Inflammation by way of axon terminals that contain neurosecretory
vesicles. These connections could be considered synapses
because the intercellular distance is less than 300 nm [2].
Introduction Paul Langerhans [3] had suspected such connections with
Langerhans cells but it was only recently confirmed that
Atopic dermatitis is an immunological disease in which the Langerhans cells are in contact with axons via both the cell
activation of immune cells induces eczema. However, these body [4, 5] and the dendrites [5]. Contacts between nerve
cells are not isolated and the interactions between these fibers and keratinocytes in the epidermis have also been
cells and both the skin and the nervous system are described [6]. In the dermis, contacts between nerve fibers
garnering increasing attention. and mast cells [7], as well as contacts between dermal
The role of the nervous system was first studied after the dendritic cells and axons [8], were observed.
clinical observations that stress was able to trigger skin Among the various neurotransmitters and neurohor-
mones, approximately 30 have been described in human
skin (Table 1) [9, 10]. Most are neuropeptides while some
L. Misery (*)
are neurohormones (prolactin, melano-stimulating hormone
University of Brest,
Brest, France [MSH], adrenocorticotropic hormone [ACTH]) or catechol-
e-mail: amines, enkephalins, endorphins, or acetylcholine. Nitric
oxide (NO) is the simplest and most evolutionarily
L. Misery
conserved neurotransmitter in the skin [11].
Department of Dermatology and Laboratory of Skin
Neurobiology, University Hospital, In the skin, neurotransmitters are synthesized by nerve
29609 Brest, France fibers and Merkel cells [12], as well as Langerhans cells,

Through cell surface receptors.e. 17]. immune cells. immune defined as the axis characterized by a hierarchy in which system. PHM A system is defined as a group of organs and/or cells that Prolactin interact and allow a common function. The CGRP inhibits contact and delays MSH NO hypersensitivity reactions by way of local effects [25].260 Clinic Rev Allerg Immunol (2011) 41:259–266 Table 1 Neurotransmitters that are involved in AD pathophysiology or apocrine glandular cells.5 [16. Nonetheless. and interac- cutaneous cells also possess receptors to the neuromediators tions between the skin. brain-derived nerve factor (BDNF). substance P [19] can inhibit antigen presentation to lymphocytes. the homeostasis between the different cell types. skin cells are able to express neuronal markers with a common language. mediate the maintenance of produce neuromediators as nerve cells. Langerhans cells and their precursors express certain Other actors of the NEICS are neurotrophins: nerve proteins that are usually encountered in cells of the nervous growth factor (NGF). protein S100 and specific neuronal enolase [14. eccrine Especially in times of stress. All NEICS cells communicate Hence. which induces the release of adrenocortico- activity is typically mediated by receptors coupled to tropic hormone (ACTH) by the pituitary gland. The inhibitory powers of CGRP have also GRH (gastrin-releasing hormone) Norepinephrine been found in vivo. There are physical linkages (such as cellular cytes. and nervous system [22]. we propose the concept of the neuro– endocrino–immuno–cutaneous system (NEICS) [13] because these three systems are closely linked anatomically and physiologically. CRH (corticotropin-releasing hormone) DOPA incubation with CGRP inhibits the induction of B7-2 in Endorphins Dopamine mice [23]. lymphocytes. which itself protein G. Neuropeptide Y The effects of neurotransmitters on skin cells are so Neurotensin numerous [27–32] that it is not possible to be exhaustive PHI here. The words of this language. Furthermore. diseases. Most of the or immune functions by the neuromediators). CGRP (calcitonin gene-related peptide) Angiotensin CGRP inhibits antigen presentation [4]. and immunity [13]. Neuromediators modulate the functions of all induces the release of cortisol by adrenocortical glands. substance P [19]. β-endorphin) [18]. i. and especially contacts between nerve fibers. and immune cells). neuro- mediators (calcitonin gene-related peptide (CGRP) [4]. gastrin-releasing peptide (GRP) [20].. and neurotransmitter receptors and have the ability to neurotransmitters and cytokines. through NK1-type ACTH (adrenocorticotropic hormone) Acetylcholine receptors on both Langerhans cells and T lymphocytes. Langerhans cells are able to produce pro. i. The Hypothalamo–Pituitary–Adrenal Axis and alpha melanocyte-stimulating hormone (αMSH) [21]) have the ability to modulate functions of Langerhans cells. the HPA axis plays a major . system. and enhances interleukin-10 Galanin Histamine production [24]. cutaneous. during the course of illness. cutaneous cell types: endothelial cells. and skin share properties and Somatostatin interact in ways that allow a common function. monocytes–macrophages.. and all immune cells (granulo. These three Substance P systems are often considered to be independent from one VIP another. mast cells). melanocytes. have anti-apoptotic effects. functional linkages (modulation of cutaneous and/ neurotransmitters remain poorly understood. This Neurokinin A Serotonin effect seems to be partly responsible for the immunosup- Neurokinin B pression induced by exposure to ultraviolet radiations [26]. and are involved in the release opiomelanocortin (precursor to MSH. However. The neuroendocrine PTH (parathyroid hormone) system. immune system. these cells are able to express are growth factors for neurons and keratinocytes [33. muscle cells.e. This mone (CRH). For example. ACTH. seems to limit the production of interleukins 1 Enkephalins Epinephrine and 12 by Langerhans cells. and of neurotransmitters and control of skin inflammation [35]. the hypothalamus produces corticotropin-releasing hor- Neuromediators exert effects on cutaneous cells. and Neuropeptides Others epidermal cells. the presence of neurosecretory chemical linkages (such as cutaneous secretion of neuro- granules has been described only in nerve endings and Merkel mediators and receptors to these neuromediators on cutane- cells. and neurotrophins 3 and 4 (NT-3 and NT-4). PGP9. nervous system. fibroblasts. These factors 15]. For example. The mechanisms by which other cells synthesize ous cells). If they are denervated. as well as during the course of certain keratinocytes. The hypothalamo–pituitary–adrenal axis (HPA axis) is which appear to be central cells linking the skin. 34].

alpha subunits 3. Nonetheless. Differences in Notably. patients with atopic dermatitis. expression levels of the Because of the endocrine regulation of skin properties. at the tissue/single cell levels and are activated in case of The role of beta-endorphin has been discussed. and 10 are generally reduced NEICS is a better term than neuro–immuno–cutaneous whereas mast cells (but not in healthy skin) show alpha3 system. and key enzymes related to levels of alpha10 subunit mRNA in lesional areas. In atopic dermatitis. especially in inflammatory and/or atopic and/ or autoimmune disorders. SP+. In these patients. 22]. of atopic dermatitis. dermatitis [59]. Because of the wide use of steroids in the treatment of In atopic dermatitis. atopy was found initially [60]. adrenal insufficiency has been observed observed. We found [62] a sion is reduced and CGRP increases the IL-13/IFNγ ratio polymorphism that was found in patients with asthma to after culture. 9. Skin innervation undergoes HPA Axis in Atopic Dermatitis many modifications. CGRP receptor expres. neurocutaneous alterations are atopic dermatitis. The earlier in atopic patients than in controls. an equivalent of HPA axis has been recently the subunit messenger RNA (mRNA) levels between described in the skin [37]. levels of prolactin [43]. was shown to be downregulated NEICS in Atopic Dermatitis by immunohistochemistry and RT-PCR in the epidermis of patients [54]. More recently. substance P or nerve growth factor The density of these receptors is decreased on both (NGF) [44] and VIP [45] are enhanced during outbreaks of keratinocytes and lymphocytes from patients with atopic atopic dermatitis. dermatitis but not in healthy subjects. No association between a particular polymorphic CGRP increases interleukin-13 and HLA-DR expression form of the human beta-2 adrenergic receptor gene and in circulating cutaneous lymphocyte-associated antigen. The kappa-opioid system. No corticosteroid synthesis. plasma cortisol levels peaked somatostatin-immunoreactive fibers disappear [39]. However. VIP+ and CGRP+ nerve fiber densities [56]. Skin cells also synthesize gluco. and there was an distribution of dermal and epidermal cells that are immu. imitate the signaling hierarchy of the HPA axis. Human skin expresses elements lesional and nonlesional skin were observed for the alpha of the HPA axis. Plasma levels of catecholamines are higher In patients with atopic dermatitis. which was independent of treatment. CGRP is also known abnormalities of the adrenergic system are not limited to to regulate Langerhans cell functions [4. Blood stress. a peripheral blood mononuclear leukocytes [46]. 9. and 10. Melatonin is decreased in the serum during outbreaks tial. The levels of some neurotransmitters fluctuate in both the skin and the blood. Indeed. 7. including pro-opiomelanocortin. CRH. Blood functional changes through the activation of β2 receptors. cell type-specific regulatory loops. In the skin of [63]. in whereas neuropeptide Y-immunoreactive dendritic cells a study on children [57]. difference in the expression levels of the alpha subunits was corticoids. while adrenergic innervation decreases and the disease itself. Immunoregulation under stressful conditions is inef- . both cell types show a sixfold Substance P enhances IFNγ and IL-4 release from increase in their KD values. Changes in mu-opiate receptor expression The nervous system plays a significant role in most were also found [55]. with higher levels of alpha3 but lower CRH receptor-1 (CRH-R1). inverse relationship between the time to peak and the extent noreactive for somatostatin is highly disrupted [40]. but not the micro-opioid system. Differen. dermatoses. The cutaneous concentration Catecholamines are known to modulate IgE-dependent of substance P decreases while the concentration of immunity [58] by potentiating IL-4-induced phenotypic and vasoactive intestinal peptide (VIP) increases [42]. the skin levels of because of abnormalities in synthesis and degradation acetylcholine are strongly enhanced [49]. an Ala 119 positive T cells in patients with atopic dermatitis but not mutation to Asp119 was discovered to cause increased in controls [48].Clinic Rev Allerg Immunol (2011) 41:259–266 261 role in chronic inflammatory disorders and atopy [36]. Based on these results. as well as polymorphism in the β2 adrenoreceptor gene was sus- TNFα and IL-10 release [47] in atopic patients. specific abnormalities seem to be related to increase [38]. sensitivity to L-phenylalanine [61]. the subunits 3. suggesting an immunomodulatory role of be seven times more frequent in intrinsic atopic dermatitis CGRP that exhibits a Th2 pattern in patients with atopic than in extrinsic atopic dermatitis. receptors. pected. which dermatitis. Expression of these elements is organized into found between extrinsic and intrinsic types of atopic functional. levels have been found to decrease in some studies [51] and increase in others [53]. appear in the epidermis [41]. and alpha5 subunit immunoreactivity [50]. CRH-driven responses of defined cutaneous cell [51] which may inhibit the development of atopic populations reproduce key features of the central HPA axis dermatitis-like skin lesions in NC/Nga mice [52]. by exerting effects on immune cells through neurotransmitters.

More notably. 85]. a Some clinical studies have demonstrated the role of model of atopic dermatitis [72]. the subgroup meta- Skin sensitivity to electric current is decreased in patients analysis on healthy and atopic disorder populations with extrinsic atopic dermatitis but not in patients with the showed that psychosocial factors had both etiological intrinsic form. We consider the second hypothesis to be decreased in atopic skin [71]. Psoralen–ultraviolet A stress in atopic diseases.7%) in combination with allergic rhinitis healthy controls [74]. which is a treatment for atopic dermatitis. neuroselective trans- of the disease [36. stress does not induce atopic BDNF levels are elevated in plasma and eosinophils from dermatitis or other dermatoses in every person. Semaphorin 3A (Sema 3A) is known to be expressed by this occurrence could be linked to genetic and immune keratinocytes and to inhibit nerve growth. Clinical evaluation revealed hypersensory sensitivity in atopics [79]. By contrast. There were 43 related Atopic Dermatitis and Skin Neurophysiology studies (in 22 articles). The influence of stress and psychological factors on the NGF and its receptor are more highly expressed in lesions skin implies that there are chemical factors that translate an than in healthy skin [66]. This phenomenon appears to be related to an and prognostic effects on atopic disorders. Vasomotor disorders (“delayed cholinergic blanch”) [81] Skin innervation is significantly greater in skin lesions of and impaired sweating function in atopics [82] are patients with atopic dermatitis than in uninvolved skin. We propose patients and BDNF is chemotactic for eosinophils in these two possible explanations. the occurrence of a patients. Neurotrophin-4 produc. with abnormalities of many mitochondria and reduced number of Schwann cells the sympathetic nervous system [83] and increased vagal suggest that these free nerve endings are activated. and food allergies subjects. The modulation [84]. . Its production is backgrounds. destructions were more catastrophic [93]. blood. The overall meta-analysis [95] exhibited positive and itch in atopics who have just been freed from eczema association between psychosocial factors and future atopic [75]. Psychosomatic Consequences and the Role of Stress mal cells [65]. presence of many pinocytotic vesicles in keratinocytes facing nerve endings with many neurovesicles suggests reciprocal interactions between nerve endings and epider. poor mental health. NGF levels are higher in lesions emotion or stress into a cutaneous lesion [64. Stress nerve fibers in the epidermis [68]. itch in patients with lesions. of which 34 evaluated the effect of psychosocial factors on atopic disorders and nine Sensory functions of the skin are modified in patients with evaluated the effect of atopic disorders on mental health. The two-point discrimination of itch is The major atopic disease assessed in these studies was significantly better in atopic dermatitis patients than in asthma (90. and hormones. induces alterations of the NEICS and HPA axis through tion by keratinocytes is also increased in lesions and its modifications of blood and skin levels of neurotransmitters expression is induced by the injection of interferon-γ [69]. First. When [67]. histamine induces itch associated with disorders as well as between atopic disorders and future burnings as opposed to pure itch in healthy subjects [76]. In patients. similar phenomenona are described inhibitors improved dermatitis and decreased the density of in the nervous system.262 Clinic Rev Allerg Immunol (2011) 41:259–266 fective in patients with atopic conditions. Acetylcholine elicits pain in healthy (4. alters events exacerbate asthma [92]. and skin [86–91]. This increased innervation is related to growth factors.3%). A gene polymorphism has been shown to be cutaneous disorder after a stress could be linked to frequently present in patients with atopic dermatitis. which is correlated with sleep Modifications of Skin Innervation in Atopic Dermatitis disorders [80]. and a mixture of pain (2. axons bulging with and an autonomic dysfunction [83]. In contrast to healthy subjects. However. neurotransmitter profiles in response to stress. Perceived stress is more intense in people with inflammatory dermatoses than in healthy subjects [94]. Sema3A alleviates more probable than the first. leading to impaired skin barrier in patients with the extrinsic form aberrant immune responses and subsequent exacerbation [77]. negative life therapy. 64]. As attributable to an abnormal sudomotor axon reflex [82] visualized using electron microscopy. The topical application of high-affinity NGF receptor a stress is experienced. skin lesions and scratching behavior in NC/Nga mice. These and correlate with clinical severity and eosinophil counts factors are probably neurotransmitters and hormones. atopic dermatitis. atopic dermatitis was more severe when innervation in atopic dermatitis [73].3%). atopic dermatitis (2. Secondly. For example. particular personality profiles and perhaps to particular especially in the intrinsic form [70].7%). cutaneous electrical stimulation preferentially evokes itch in atopics [78]. After an earthquake in epidermal Sema3A and NGF levels and modulates epidermal Hanshin (Japan).

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