Skin and the Nervous System: Stress, Itch and More
Tur E (ed): Environmental Factors in Skin Diseases. Curr Probl Dermatol. Basel, Karger, 2007, vol 35, pp 136–145
Pathogenesis of Stress-Associated Skin Disorders: Exploring the Brain-Skin Axis
Departments of Physiology and Neurosurgery, Soroka University Hospital andZlotowski Center of Neuroscience, Ben-Gurion University, Beersheva, Israel
Abstract The association between psychological stress and skin diseases is well known from
clinical practice and the literature. Stress – a complex adaptive response – acts on differentlevels of the nervous system and affects many organ systems. We review here the availableknowledge regarding the possible mechanisms underlying stress actions in the pathogenesisand course of skin diseases.
It is well acknowledged that psychological stress plays an important role in
the pathophysiology of numerous skin disorders [1, 2]. However, the strength ofassociation between stress responses and the onset, recurrence or exacerbationof various skin diseases varies [1, 2] (table 1). The skin disease best known asstress associated and by far the most intensively studied for this association ispsoriasis, with 40–60% of cases triggered by stress [3–7]. Moreover, psycholog-ical distress has a detrimental effect on treatment outcome in patients with psori-asis . Interestingly, among pediatric patients with psoriasis, stress has an evenmore important role in disease exacerbation compared to adults . Anothercommon inflammatory skin disease, known to be associated with psychologicalstress is atopic dermatitis (AD) – a common pruritic skin disorder. Both childrenand adults with AD have higher anxiety levels than those without, and it is wellknown that psychological stress brings on attacks or exacerbates skin symptoms[10–14]. In patients with c1 esterase inhibitor deficiency, suffering fromurticaria and angioedema, stress has been shown to be an important triggeringfactor . Moreover, adrenergic urticaria, a separate rare clinical entity, appearsduring periods of emotional stress or exercise [16, 17]. Stress is often cited as
Table 1. Stress-associated skin disorders
playing a role in acne vulgaris flares , as well as in reactivation of latent her-pes simplex infection [19, 20]. Although the association between stress and skindiseases has been well known for decades, the mechanisms underlying stress-induced dermatopathologies are not fully understood. Here, we will review theup-to-date knowledge of mechanisms proposed to underlie stress-induced skindisease, from stress perception by the brain’s cerebral cortex to the appearance ofskin lesions. Since the brain and the skin communicate in both directionsthrough the immune and the neuroendocrine systems, stress effects on skin dis-ease must be mediated through these systems. All skin diseases mentioned hereare inflammatory disorders, except herpes simplex infection, which is a latentinfectious disease, and for the activation of HSV some attenuation of theimmune system needed. Thus, when searching for understanding of the mecha-nism underlying the role of stress action in skin diseases, we should understandthe role of stress-induced activation of the neuroendocrine system in the inflam-matory cascade and the skin immune system (fig. 1). Hypothalamic-Pituitary-Adrenal Axis
During acute stress response, the paraventricular nucleus of the hypothala-
mus releases corticotropin-releasing hormone (CRH). CRH then acts on thepituitary gland to induce a release of adrenocorticotropic hormone (ACTH),which in turn causes the adrenal cortex to release cortisol. How elevatedcortisol levels protect the organism under stress is not completely understood,but in conditions of cortisol deficiency, stressful events like trauma or infectionresult in hypotension, shock, and death. Moreover, cortisol is a very potent
Pathogenesis of Stress-Associated Skin Disorders
Fig. 1. Schematic presentation of the brain-skin axis. Stressful input perceived by the
cerebral cortex leads to CNS stress response and activation of the HPA axis and PNS whichmay affect the skin directly or through modulation of the immune system (see text for details).
anti-inflammatory molecule, and is widely used in pharmacy for this property,especially in dermatology, as a fundamental ingredient in local and systemicremedies. So, how may the activation of the HPA axis harm the skin? Recentstudies in rats, demonstrated the involvement of CRH receptors (CRHR) instress-induced exacerbation of chronic contact dermatitis . In this study, theauthors induced chronic contact dermatitis in rats by local exposure to 2,4,6-trinitro-1-chlorobenzene. In addition, rats were exposed to a 1-hour periodof electric foot-shock following intraperitoneal administration of CRA1000,selective CRHR type 1 (CRHR1) antagonist, or vehicle everyday for 9 days. Histological examination of the skin showed that the epidermis significantlythickened and the number of mast cells in the dermis significantly increased byrepeated exposure to stress, and that these changes were blocked by CRA1000.
These results suggest that CRHR1 located in the brain, skin or both is involvedin the stress-induced exacerbation of chronic contact dermatitis in this animalmodel. A recent clinical study by Richards et al.  support the notion thatdisturbances in the HPA axis are involved in skin diseases. In their study, 40patients with chronic plaque psoriasis and 40 age-matched healthy controlsexperienced three randomly presented acute psychological stressors (cognitive,emotional and social). While in healthy subjects there was a significant correla-tion between pulse rate and serum cortisol level following the social perfor-mance stressor, no such correlation was found in the psoriasis group. Moreover,patients who believed that their psoriasis was highly stress responsive had sig-nificantly lower salivary cortisol levels at baseline and lower serum cortisol lev-els following the social performance stressor than patients who believed thatstress had no impact on their disease. In contrast, the pulse rate response to thestressors was similar in the two groups. This study suggested that patients withpsoriasis, and in particular those whose disease appears to be stress-associated,exhibit an altered HPA response to acute social stress. The implication is thatsuch patients may perhaps be primed to flares of their psoriasis. Whether this isgenetically predetermined and/or a consequence of the distress of living withpsoriasis remains to be determined. Recently, a fully functional peripheral equiv-alent of the HPA axis was demonstrated ; normal human scalp hair folliclesdirectly respond to CRH stimulation in a strikingly similar manner to what isseen in the classical HPA axis, including synthesis and secretion of cortisol andactivation of prototypic neuroendocrine feedback loops, as demonstrated by thedownregulation of follicular CRH expression with the glucocorticoid receptoragonist, hydrocortisone. Moreover, the influence of a local HPA axis or ratherCRH-proopiomelanocortin axis in alopecia areata (AA) was recently investi-gated . In this study, the immunohistochemical analysis of the expressionlevels of CRH and proopiomelanocortin peptides, including the ACTH and a-melanocyte-stimulating hormone, in a number of AA lesions and normal scalp(as control) showed that the epidermis and pilosebaceous units of normal scalpstained weakly with CRH, ACTH and a-melanocyte-stimulating hormone,whereas those from the affected sites of the AA group showed intense expres-sion of the peptides. Hypothalamic-Pituitary-Adrenal Axis and Immune SystemSo far, we discussed the direct effect of HPA activation during stress on
skin disease. However, HPA axis activation modulates the function of theimmune system as well [for review, see 25]; for example, in a recent study acorrelation between the degree of stress and the levels of IgE and Th2 wasfound in patients with AD .
Pathogenesis of Stress-Associated Skin Disorders
Long-Term Effects of StressStudies in animals and humans suggest that stress is associated with long-
term alterations in brain function and structure. Studies in animals showed long-term dysregulation in stress-responsive systems, including the norepinephrine(NE) and HPA axis systems. The HPA axis and cortisol systems have been shownto be dysregulated in posttraumatic stress disorder, and glucocorticoids, which arereleased during stress, were shown in animal studies to be associated withreduced number of neurons in the hippocampus, a brain area that plays an impor-tant role in learning and memory. More studies are awaited to reveal the mecha-nism underlying altered HPA response in psoriatic patients and its possiblerelation to dysregulation of the HPA axis in posttraumatic stress disorder patients. Peripheral Nervous System Sympathetic SystemThis major arm of the stress response within the peripheral nervous system
(PNS) originates from the ‘locus coeruleus/norepinephine system’ within thecentral nervous system (CNS). Its activation causes central sympathetic dis-charge and peripheral sympathetic outflow, resulting in secretion of NE fromnerve fibers terminals, and adrenalin (or epinephrine), which is secreted fromthe adrenal medulla. During the stress response, both molecules are invariablypresent in the circulation. What effect has sympathetic activation on the skin andhow may it be related to skin diseases? Sympathetic activation via its actions oncutaneous blood vessels is important for thermoregulation and response to heatand cold stress. When core temperature is reduced, NE is released and acts toconstrict cutaneous vessels. However, during a rise in core temperature (such asmay occur with environmental stress), the control of cutaneous blood flowbecomes more complicated . The main mechanism involved in response toheat stress in nonacral regions of skin is sympathetically mediated active vasodi-latation. Details regarding neurotransmitters responsible for this vasodilatationare not completely understood, but the best evidence existing now points to sym-pathetically released cholinergic co-transmitter  and nitric oxide . Casereports showing that injury to cutaneous nerves result in complete remission ofpsoriasis at the distal site support an important role for nerve terminals at thePNS in the pathogenesis of psoriasis. In one such case report , a completeunilateral remission was observed in a patient with chronic plaque psoriasis afteracute accidental injury of the ipsilateral brachial plexus. The psoriasis reap-peared as the nerve plexus recovered. Substance P (SP) was proposed as onepotential neural mediator in psoriasis and psoriatic arthritis . Emotionalstress was shown to cause a release of SP from neurons . Notably, cutaneous
nerves and SP play an important role in the pathogenesis of AD, another inflam-matory skin disease, through altered patterns of cutaneous innervations andabnormal expression of neuropeptides in the lesional skin . SP has been par-ticularly implicated, because increased numbers of nerve fibers containing SPare found concomitantly with a decrease in SP cutaneous levels in lesioned skinof AD patients. Furthermore, the skin of AD patients is hyposensitive to intra-dermal injection of SP, further supporting its role in inflammatory skin response[34, 35]. Increased plasma levels of SP and nerve growth factor, which modu-lates the synthesis of SP, were also found in AD patients . These findingssuggest that specific neurogenic factors modulate the systemic allergic responsein AD. The mechanisms of SP action in these diseases are most probably relatedto the activation of mast cells to secrete specific cytokines, chemokines andtumor necrosis factor-␣ . Interactions between the sympathetic nervous sys-tem with various components of the immune system have been reported; forexample, acute stress was shown to increase migration of dendritic cells as partof delayed type hypersensitivity reaction , and animal studies showed thatacute stress initially increases trafficking of all major leukocyte subpopulations toa site of immune activation. Tissue damage-, antigen-, or pathogen-driven chemoat-tractants subsequently determine which subpopulations are recruited more vig-orously. Such stress-induced increase in leukocyte trafficking may enhanceimmunoprotection during surgery, vaccination, or infection, but may also exac-erbate immunopathology during inflammatory or autoimmune (psoriasis orarthritis) diseases . Cholinergic System and Other Neurotransmitter SystemsAdditional neurotransmitter systems are known to be involved in the stress
response. Besides the sympathetic, adrenergic arm, the cholinergic arm origi-nating from the vagal nucleus of the brain stem is crucially involved in stressresponses. Furthermore, adrenergic and cholinergic transmitter systems withinthe brain are also activated during stress, thus influencing the PNS. The braincholinergic system, including both muscarinic and nicotinic subsystems, playsan important role in a variety of cognitive functions including attention, learn-ing and memory . During the past decade, several groups [38–40] showedthat following stress, cholinergic stimulation triggers rapid induction of thegene encoding the transcription factor c-Fos. This protein, in turn, serves as aselective regulator for numerous transcriptional changes affecting the levels ofproteins, including those involved in acetylcholine metabolism . In addi-tion, mechanisms like alternative splicing involve neuritic replacement ofsynaptic acetylcholinesterase with the normally rare ‘readthrough’ variant,leading to altered cholinergic balance and structural changes . The skin hasabundant cholinergic system with fully developed enzymatic machinery known
Pathogenesis of Stress-Associated Skin Disorders
to play a central role in blistering skin diseases [for review, see 43]. Interestingly, in a recent, large case control study, smoking was shown to bestrongly associated with pustular psoriasis . Thus, a plausible hypothesiswould be that in the skin, like in other body organs (e.g. brain , blood andbone marrow , testis ), stress induces changes in local cholinergic sys-tem which alter inflammatory responses . It was shown, that vagal stimula-tion may inhibit inflammatory responses through activation of nicotinicacetylcholine receptors . Other local transmitter systems (e.g. serotonergic)may also be important . Biological Barriers
Animal studies provide evidence that psychological stress can induce
blood-brain barrier disruption [50, 51] thus promoting long-term brain dys-function . Interestingly, stress induced alterations in epidermal permeabilitybarrier homeostasis have been shown in both animals and humans , to bemediated by endogenous glucocorticoids. The mechanisms underlying stress-induced increase in epidermal barrier permeability are related to the inhibitionof epidermal lipid synthesis, resulting in decreased lamellar body formationand secretion, as well as decreased corneodesmosomes, both compromisingpermeability barrier homeostasis and stratum corneum integrity . Conclusion
Stress is a complex biological response known to be associated with vari-
ous skin diseases. Accumulating clinical and experimental data provide evi-dence for a complex net of cellular and molecular mechanisms involved in thepathogenesis skin disease under stress. Activation of the HPA axis and the sym-pathetic system are the most studied so far, but other possibilities have to beconsidered, like involvement of the cholinergic system and impairment of epi-dermal barrier function. Exploring these pathways will offer new strategies inthe treatment of common skin disorders. References
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Lev Pavlovsky, MD, MScDepartments of Physiology and NeurosurgeryZlotowski Center of NeuroscienceBen-Gurion UniversityIL–84105 Beersheva (Israel)Tel. ϩ972 8 6479 884, Fax ϩ972 7 6479 883, E-Mail firstname.lastname@example.org
Pathogenesis of Stress-Associated Skin Disorders
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