Clinics in Dermatology (2012) 30, 280–285

Psychological stress and epidermal barrier function

Edith Orion, MD a,⁎, Ronni Wolf, MD b
a
Psychodermatology Clinic, Kaplan Medical Center, Rehovot 76100, Israel
b
Dermatology Unit, Kaplan Medical Center, Rehovot 76100 , Israel
(affiliated to the Hebrew University—Hadassah Medical School, Jerusalem, Israel)

Abstract The skin is the organ that acts as a barrier between the outer and inner environments of the
body. It is thus exposed not only to a wide variety of physical, chemical, and thermal insults from the
outside world but also to inner endogenous stimuli. Stress, once an abstract psychologic phenomenon,
has taken research's center stage in recent years. The “mind–body connection” is now less of an obscure
New Age term and more of an elaborate physiologic pathway by which bilateral communication occurs
between body and brain. Dermatologists and dermatologic patients have long acknowledged the effect
of stress on the skin and its capability to initiate, maintain, or exacerbate several skin diseases. Because
disruption of epidermal barrier integrity may be important in the development of some common skin
diseases, it is crucial to understand its vulnerability to psychologic stress.
© 2012 Elsevier Inc. All rights reserved.

Introduction movement of water. 2 It also has an effect on the epidermal

The main function of the epidermis is to regulate
epidermal permeability and to act as a physical, chemical,
and antimicrobial defense system through the action of the
outermost layer of the epidermis, the stratum corneum (SC).
A critical feature of the epidermis, permeability barrier
homeostasis, is maintained by the exocytosis of lamellar
bodies content at the stratum granulosum–SC interface.
After secretion, colocalized hydrolytic enzymes process
lamellar body-derived polar lipids into a more nonpolar
mixture of ceramides, free fatty acids, and cholesterol. When
present in an anhydrous, acidic environment, which also
contains small amounts of cholesterol sulfate, these lipids
transform into multilamellar membrane sheets. 1 The local-
ization of these highly hydrophilic lipids within the
extracellular domains of the SC inhibits the outward
⁎ Corresponding author. Fax: +972-3-643-6086.
E-mail address: eorion@013.net (E. Orion).
antimicrobial defense barrier. 3
Impairments in skin barrier function have been found in
several common chronic skin disorders, including psoriasis
and atopic dermatitis, and also have been shown to
exacerbate allergic and irritant contact dermatitis. 4 The
abnormality in cutaneous permeability barrier homeostasis
induced by psychologic stress (PS) could have adverse
effects on skin function, leading to pathophysiologic
alterations, thus ameliorating or even generating those
diseases. A growing body of evidence suggests that not
only physiologic stress but also PS can influence the
epidermal barrier function.
PS can affect skin permeability in animals
Studies in rodents found that imposition of different forms
of PS provoked an abnormality in permeability barrier
homeostasis. One of the pioneer works clarifying the
relationship between PS and skin barrier homeostasis showed
the effect of psychologically stressful stimuli (immobilization

0738-081X/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.clindermatol.2011.08.014
Psychological stress and epidermal barrier function
and crowded environment) on skin barrier function in rats.
Immobilization altered barrier recovery, and damage was
more obvious in cases of longer stress exposures, suggest-
ing that the degree of stress influence is due to the “dose” of
stress. 5 Diazepam and chlorpromazine (tranquilizers)
blocked the influence of immobilization stress on barrier
homeostasis, suggesting that emotional stress was indeed
involved in the process. Also of importance was the
observation that male and female rats showed same effect
of immobilization on barrier homeostasis, indicating that
sex hormones probably do not play a significant role, while
stress hormones take center stage.
Researchers in a later study 6 demonstrated that provoking
PS in hairless mice by transferring them to a different cage
also delayed barrier recovery rates. Pretreatment with
chlorpromazine (a phenothiazine sedative) before the
transfer of animals restored the kinetics of barrier recovery
toward normal. The effect of the drug suggested that PS was
the basis for this alteration in barrier homeostasis.
To determine the mechanism by which PS alters barrier
recovery, plasma corticosterone levels were measured and
showed a marked increase after the animals were transferred
to the new cages. Pretreatment with the sedative chlorprom-
azine blocked this increase. When corticosterone was
systemically administered, a similar delayed barrier recovery
was noticed. Pretreatment with a glucocorticoid receptor
antagonist (RU-486) also blocked the delay in barrier
recovery produced by stressful stimuli. 6 These data proved
that endogenous glucocorticosteroids are important in the
linkage between PS and derangements in barrier homeostasis.
PS can affect skin permeability in humans
After the effect of PS on barrier homeostasis in rodents
was demonstrated, it was time to discover its effect on human
skin. An almost parallel study demonstrated that acute PS
and physiologic stress can both inhibit recovery of skin
barrier function in humans. Although stress-induced impair-
ment of barrier function recovery in mice depends on
glucocorticoids released with stress, this study found no such
relationship, probably because the stressful trigger did not
generate a severe degree of stress, thus producing a smaller
rise in corticosteroids compared with the animal models. 4
Also of interest is that in contrast to impairmnt in skin barrier
function recovery after both types of stress (physiologic and
psychologic), an increase in baseline transepidermal water
loss (TEWL) was found only in response to PS and only in
the skin of the face. This study demonstrated increases in
circulating levels of interleukin-1 (IL-1β), tumor necrosis
factor-α, and IL-10 in response to PS, reaching peak levels
up to 1 hour or more after acute stress. 4
Another group of researchers investigated the relationship
between PS and epidermal permeability barrier function in
medical, dental, and pharmacy students without coexistent
281
skin disease. The stressor chosen was their final examina-
tions (a bit of humor is always useful!). The students
demonstrated a decline in permeability barrier recovery
kinetics after barrier disruption by cellophane tape stripping
that paralleled an increase in perceived PS. The more stressed
the student felt, the longer it took his or her permeability
barrier function to recover. The greatest deterioration in
barrier function occurred in those participants who demon-
strated the largest increases in perceived PS. 7 Barrier
function returned to normal coincident with a reduction of
PS during a subsequent vacation period. Those results
demonstrated that PS-induced alterations in barrier function
could represent a clinically relevant mechanism that
contributes to disease expression in humans.
The mechanisms
The concept of PS has traditionally been linked to
physical mechanisms of cutaneous damage inflicted by the
patient, such as scratching or picking. In contrast, science has
been unable to explain how an abstraction such as PS could
generate structural and functional changes in the epidermis
that predispose it to disease. 8
The main adaptive response to sustained systemic stress is
mediated by the hypothalamic-pituitary-adrenal (HPA) axis.
This response begins with the stress-induced hypothalamic
production of corticotropin-releasing factor (CRF), which
activates CRF receptor type 1 in the anterior pituitary and
induces the production and release of adrenocorticotropic
hormone, which is derived from proopiomelanocortin. The
expression of CRF and proopiomelanocortin can also be
stimulated by proinflammatory cytokines, thus involving the
immune system in the central regulation of the HPA axis.
Pituitary-derived adrenocorticotropic hormone stimulates
adrenocortical production and secretion of glucocorticoids,
such as the steroid hormone cortisol (in humans) and
corticosterone (in rodents), so the product of a stressful
stimulus would be a rise in systemic glucocorticoids. 9 These
glucocorticoids counteract the effects of stressors, suppress
the immune system, and attenuate the functional activity of
the HPA axis by feedback inhibition of CRF and
proopiomelanocortin expression.
The question is how the systemic stress reaction in-
fluences the disruption of the epidermal barrier function.
Research has shown that several physiologic changes
provoked by PS can be responsible for the alteration of
barrier permeability. Some investigators believe that the
stress-induced release of neuroimmune substances adversely
influences cutaneous homeostasis through activation of
immunologic or inflammatory processes in deeper skin
layers. 8,10 There are studies, however, that support an
alternate or parallel pathway—that stress adversely affects
permeability barrier homeostasis by increasing systemic
glucocorticoid levels. 4,6
282
Role of glucocorticosteroids
Glucocorticoids, which rise after stressful stimuli, may
be important in the disruption of epidermal permeability
barrier and function. This proposed scheme is supported by
the fact that:
1. the induction of PS is associated with increased
endogenous glucocorticoid production in both rodents
and humans, 6,11,12
2. the administration of systemic glucocorticoids ad-
versely affects barrier homeostasis 6 and epidermal cell
proliferation in rodents, 13 and
3. the coadministration of the steroid hormone antagonist
RU-486, along with PS, blocks development of the
barrier abnormality. 6
It is of importance to note, however, that serum and
salivary cortisol levels do not always change with altered PS
in humans. 14
Long-term glucocorticoid treatment decreases epidermal
proliferation and differentiation. 15,16 Even short-term glu-
cocorticoid treatment inhibits epidermal lipid synthesis,
resulting in decreased production and secretion of lamellar
bodies and also in impaired production of lamellar
membranes in the SC. 17 Epidermal de novo synthesis of
cholesterol, fatty acids, and ceramides is required for the
formation of lamellar bodies, and secretion of the lamellar
bodies restores the extracellular lamellar membranes that
mediate the barrier function the SC. 18
Topical treatment with a mixture of physiologic lipids,
which mimic the SC lipid composition, normalizes perme-
ability barrier homeostasis in glucocorticoid-treated mice,
linking the glucocorticoid-induced reduction in epidermal
lipid synthesis to the delay in barrier recovery. 17 Application
of exogenous physiologic lipids, which normally have no net
effect on barrier recovery, normalizes barrier recovery
kinetics and SC's integrity in PS-affected skin. This proves
that the deficiency of lipids underlies the abnormality in
permeability barrier homeostasis. 19
Similar to glucocorticoid, PS thus inhibits epidermal lipid
synthesis, resulting in a decline in the production and secretion
of lamellar bodies, coupled with a reduction in the amounts of
lamellar membranes in the SC. Similar to glucocorticoid, PS
can also decrease the SC's integrity. 19 The suppression of
epidermal lipid synthesis by PS is mediated by signaling
mechanisms that needs to be elucidated.
PS can also cause a decrease in SC's integrity 19 through a
reduction in the length and number of corneodesmosomes. 20
Differentiation-specific proteins of the corneocyte envelope
(desmoplakin, envoplakin, desmoglein 1) are corneodesmo-
somes constituents and might decrease after stress. This
hypothesis was proved when desmoglein 1 was investigated. 19
In summary, the abnormalities in permeability barrier
homeostasis and SC integrity induced by PS could both be
E. Orion, R. Wolf
mediated by increased endogenous glucocorticoid. 6 In
addition, PS-induced abnormalities in epidermal prolifera-
tion and differentiation are consistent with known effects of
increased glucocorticoid. 19 In the epidermis, the PS-induced
abnormalities are mimicked by short-term topical and
systemic glucocorticoid treatment, which also decreased
epidermal cell proliferation and thickness. 17 Also, PS-
induced decrease in lipid synthesis and lamellar bodies'
production could be glucocorticoid-mediated, because
glucocorticoid similarly inhibits these parameters, and
topical treatment with exogenous lipids normalizes perme-
ability barrier homeostasis and SC integrity in glucocorti-
coid-treated animals, indicating a similar pathophysiologic
role for glucocorticoid in reduced lipid production. 17,19 Most
epidermal changes induced by PS seem to be mimicked by
glucocorticoid treatment, suggesting that the increase in
glucocorticoid during PS is a major factor in the production
of those changes.
Role of neuropeptides
Chronic or repetitive PS seems to alter cutaneous immune
response. 18 Clinical examples for this phenomenon are
abundant; for example, PS in students during examination
periods may affect antibody production to hepatitis vaccine.
Stress effects on delayed-type hypersensitivity responses,
including modification of delayed-type hypersensitivity in
depression and other psychologic conditions, have also
been described. 8
The nervous system and the immune system share
specific communication molecules that originate in both
systems 8 and have bidirectional influences. The peripheral
nervous system and the skin are also connected via free nerve
endings that extend to the epidermis. These afferent nerves
serve as neurosecretory effectors. 21 Descending autonomic
fibers can antidromically release neuropeptides within or
near the epidermis during increased PS. 8 These neuropep-
tides can therefore alter barrier homeostasis in the deeper
epidermal levels by provoking inflammation and immuno-
logic abnormalities. 7 The pathogenic role of neuropeptides is
supported by (1) substance P and vasoactive intestinal
peptide levels change in the involved skin of atopic
dermatitis and psoriasis, 22-25(2) substance P and vasoactive
intestinal peptide are known keratinocyte mitogens, 10,26,27
and (3) cutaneous nerves can activate Langerhans cells. 28
Cutaneous neuropeptides are therefore likely to be important
in the intermediary signalling process that connects the
neuroendocrine system with immune and organ-specific
processes, but certainly, further research is needed.
Impaired antimicrobial defense barrier
The natural antimicrobial defenses of the skin also
involve elements of the innate immune response such as
the production of antimicrobial peptides, lipids, Toll-like
receptors, proinflammatory cytokines, and chemokines. 29
Psychological stress and epidermal barrier function
Multiple studies suggest that sustained PS can adversely
affect immune surveillance. 30 There is evidence that PS
compromises host defense against bacterial and viral
infections in humans and in experimental animals. 31,32 As
mentioned, the influence of PS or endogenous glucocorticoid
increase on cutaneous permeability barrier function can be
ascribed to an inhibition of epidermal lipid synthesis, leading
to decreased production of epidermal lamellar bodies.
Because human epidermal lamellar bodies deliver endoge-
nous lipids, desquamatory enzymes, and antimicrobial
peptides (AMPs) to the SC interstices, a decrease in its
production contributes also to an impairment of the
antimicrobial barrier function of the epidermis and adnexa. 3
The decrease in epidermal and adnexal AMPs production is
sufficient to increase the severity of infections by group A
Streptococcus pyogenes. 3 Thus, the PS-induced decline in
AMPs could account for the association between PS and the
reported increased risk of PS-induced cutaneous infections.
The clinical implications
The mentioned laboratory studies may explain the clinical
observations that PS has an important role in the initiation
and aggravation of some skin diseases through disruption of
epidermal barrier integrity and function. 33 Impaired epider-
mal barrier function is a hallmark feature of two of the most
common inflammatory and stress-related skin diseases,
psoriasis and atopic dermatitis (AD). 7,34,35 For both of
these inflammatory skin disorders, the degree of epidermal
barrier disruption correlates with severity of presenta-
tion. 35,36 The potential relevance of increased glucocorticoid
production caused by PS is supported by the presence of
elevated serum cortisol levels in patients with psoriasis
during acute exacerbations 37 and by the clinical observations
that flares of psoriasis and AD can frequently be triggered by
the administration of exogenous steroids. 38
The SC of mammalian epidermis has several protective
functions and comprises a heterogeneous structure of
enucleated corneocytes embedded in a lipid-enriched,
extracellular matrix important for the permeability barrier.
The extracellular matrix also contains several peptides that
contribute to the antimicrobial defense property of the
epidermal barrier. 39
The permeability and antimicrobial barriers of the
epidermis may not be discrete but rather coregulated and
even interdependent functions. 39 Because PS can alter both
properties of the barrier, its relevance in some skin diseases
featuring those defects is obvious.
Atopic dermatitis
As mentioned, sustained PS aggravates permeability
barrier function in humans, is a well-known precipitant of
AD, 40 and is a cause of resistance to therapy. Although the
283
defect in epidermal permeability in AD skin has long been
regarded as the downstream consequence of a primary
immunologic abnormality, some researchers now propose
that the defective permeability barrier is not merely an
epiphenomenon, but rather the “driver” of disease activity. 41
The putative mechanism for the negative effects of PS is
glucocorticoid-mediated inhibition of synthesis of the
epidermal lipids that mediate barrier function, including
ceramides, free fatty acids, and cholesterol. 3 We also know
that skin colonization with Staphylococcus aureus is a
common feature in AD, 42 and overt secondary infections are
well-known complications. Apart of Staphylococcus spp,
AD patients are more susceptible to widespread cutaneous
viral and dermatophytic infections. 41
In AD, an impaired permeability barrier alone predisposes
to pathogen colonization because of reduced levels of free
fatty acids and sphingosine (ceramide metabolite), which
exhibit potent antimicrobial activity. Surface proteins of S
aureus can, in turn, downregulate epidermal free fatty acids
production, thereby aggravating permeability and antimicro-
bial function in parallel, which could further facilitate
microbial invasion. 41
In addition, two AMPs are downregulated in a T helper
cell 2–dependent fashion. 43 One of the AMPs, the human
cathelicidin product LL-37, is required for normal epidermal
permeability barrier function and is also important for the
integrity of extracutaneous epithelia. 39 Thus, the decrease in
LL-37 likely amplifies the barrier defect in AD. 41
If PS can alter barrier permeability and antimicrobial
epidermal defenses, and if the defective barrier function has a
major pathogenic role in the development of AD, PS should
be given its rightful consideration when formulating therapy
for AD patients.
Psoriasis
In a survey of 5600 patients with psoriasis, more than
30% reported they believed that stress triggered their
psoriatic flares, 44 and in a study of 2144 psoriatic patients,
40% associated the appearance of psoriatic plaques with
concurrent life stressors. 45 One of the concepts for the
pathogenesis of psoriasis suggests that the integrity of the
epidermal barrier and its effective function are important
factors in the regulation of epidermal DNA synthesis. Its
dysfunction may lead to epidermal hyperproliferation, a
key feature of psoriasis. 29 Although the clinical effects of
PS on initiation and exacerbation of psoriasis are well
documented, 33 and although the importance of epidermal
integrity disruption in disease process is also documented,
little is known concerning the actual effects of PS on
epidermal barrier integrity in psoriasis. Many studies
speculate on the mechanisms by which PS alters psoriatic
skin's barrier function. Some of these studies prove that PS
can alter permeability barrier homeostasis, a known feature
in psoriasis pathology 7 through inhibition of epidermal
lipid synthesis. 19 PS could also change the threshold for
284
physical insults (eg, the Koebner phenomenon) or could
prolong the recovery from such insults, resulting in
enhanced epidermal mediator production. 46 The net effects
would be a lowered threshold for disease induction, or
interference with disease resolution. 7
Conclusions
Although parts of the puzzle are still not in place, science
has now proven that PS can affect the skin and can generate
or exacerbate disease through disruption of epidermal barrier
permeability and function. Many key issues of understanding
the exact mechanisms of that effect still need to be
elucidated; nevertheless, the validation of this “mind–skin”
connection reinforces the need for us to address this issue
when formulating the treatment of our patients. Stress and
stressful events should be looked for and talked about
because they can be the fueling source of some common skin
diseases, and psychologic and psychopharmacologic ap-
proaches should be advised.
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