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The intricate relationship between stress and skin conditions has been documented since ancient times. Recent clinical observations also link psychological stress to the onset or aggravation of multiple skin diseases. However, the exact underlying mechanisms have only been studied and partially revealed in the past 20 years or so. In this review, the authors will discuss the recent discoveries in the field of “Brain-Skin Connection”, summarizing findings from the overlapping fields of psychology, endocrinology, skin neurobiology, skin inflammation, immunology, and pharmacology.
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Inflammation & Allergy - Drug Targets, 2014, 13, 177-190 177
Brain-Skin Connection: Stress, Inflammation and Skin Aging
Ying Chen* and John Lyga
Global R&D, Avon Products. 1 Avon Place, Suffern, NY 10901, USA
Abstract: The intricate relationship between stress and skin conditions has been documented since ancient times. Recent
clinical observations also link psychological stress to the onset or aggravation of multiple skin diseases. However, the
exact underlying mechanisms have only been studied and partially revealed in the past 20 years or so. In this review, the
authors will discuss the recent discoveries in the field of “Brain-Skin Connection”, summarizing findings from the
overlapping fields of psychology, endocrinology, skin neurobiology, skin inflammation, immunology, and pharmacology.
Keywords: Inflammation, skin aging, stress response.
INTRODUCTION
Psychological stress arises when people are under
mental, physical, or emotional pressure. It arises when the
individual perceives that the pressure exceeds his adaptive
power. It is perceived by the brain and stress hormones such
as corticotropin-releasing hormone (CRH), glucocorticoids,
and epinephrine are released. This triggers a wide range of
physiological and behavior changes and responses that try to
adapt the body to the stress [1]. However, if the stress
responses are inadequate or excess, they may trigger adverse
physiological events [2]. It has been shown that stress can
trigger and/or exacerbate multiple conditions, including
cardiovascular disease [3, 4], migraine [5], multiple sclerosis
[6], epileptic seizures [7], and neurodegeneration [8].
Recent research has confirmed skin both as an immediate
stress perceiver and as a target of stress responses. As the
largest organ of the body, skin plays important barrier and
immune functions, maintaining homeostasis between external
environment and internal tissues. It is composed of two major
layers: epidermis and dermis. The epidermis is a continuously
renewing layer where basal proliferating keratinocytes
gradually differentiate, move up and eventually slough off the
surface. The outermost layer of the skin epidermis, the stratum
corneum (SC), is composed of dead and flattened corneocytes
embedded in a matrix of lipids. Corneocytes contain numerous
keratin filaments bound to a peripheral cornified envelope
composed of cross-linked proteins. While the flattening of the
secreted lipids vesicles form intercellular lamellar disks, which
then disperse and join together to form multiple, continuous
membrane sheets [9, 10]. The dermis is composed of
fibroblasts and extracellular matrix which provides elasticity
and tensile strength [11].
In this review, we will summarize the recent findings on
how brain and skin communicate with each other, how the
skin reacts to the stress by activating the endocrine and
immune systems, and the negative impact of chronic stress
on skin health.
*Address correspondence to this author at the Global R&D, Avon Products.
1 Avon Place, Suffern, NY 10901, USA; Tel: 845-369-2522;
Fax: 845-369-2405; E-mail: ying.chen@avon.com
STRESS MEDIATORS AND EFFECTOR CELLS
Skin is the primary sensing organ for external stressors,
including heat, cold, pain, and mechanical tension. Three
classes of receptors (thermoreceptors for heat and cold,
nociceptor for pain and mechanoreceptors for mechanical
changes) are responsible for transmitting the outside signals
to the spinal cord, and then to the brain [12]. The cutaneous
sensory fibers also convey changes in temperature, pH, and
inflammatory mediators to the central nervous system
(CNS). The nerve terminals are often associated with
receptors indicating close interaction [13]. The brain
responds to these signals, which in turn influence the stress
responses in the skin.
Skin and its appendages are not only targets of key stress
mediators, they are also a local source for these factors
which induce various immune and inflammation responses.
In this section we will discuss key players in mediating the
stress response from both the central nervous system as well
as the resident skin cells.
Central HPA Axis
Stress conditions exert their effects to skin mainly
through the hypothalamic-pituitary-adrenal (HPA) axis.
Upon sensing stress, neurons in the hypothalamus secrete
corticotropin-releasing hormone (CRH), which is transported
to the pituitary gland, where it binds to the CRH receptor
type-1 (CRH-R1) and stimulates the secretion of proopiome-
lanocortin (POMC)-derived neuropeptides, including α-
melanocyte stimulating hormone (α-MSH), β-endorphin, and
adrenocorticotropin (ACTH). In turn, ACTH travels to the
outer layer of adrenal cortex through the bloodstream, binds
to the MC2 receptors (MC2-R), and stimulates production of
glucocorticoids (GC) including cortisol and corticosterone.
Cortisol is the primary stress hormone in human that
regulates a wide range of stress responses [14]. Cortisol
works by binding to the glucocorticoids receptor (GR),
which undergoes conformation change, dissociates from the
heat shock protein binding complex, translocates to the
nucleus, and affects gene expression through binding
domains on gene promoter regions or direct interactions with
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© 2014 Bentham Science Publishers
178 Inflammation & Allergy - Drug Targets, 2014, Vol. 13, No. 3 Chen and Lyga
transcription factors like Activating Protein 1 (AP-1) and
nuclear factor-κB (NF-κB) [15, 16].
Normally cortisol levels undergo daily oscillation
regulated by the internal circadian clock system, with peak
level at early morning and lowest point around midnight [17,
18]. Stress can significantly disrupt cortisol level and
oscillation curve. It was shown that in mice under restraint
stress, there is diurnal dysregulation of HPA-axis activation
resulting in a 4-fold increase in plasma corticosterone [19].
Under stress conditions, significantly up-regulated cortisol
can have a major impact on the immune system (mainly
being immunosuppressive), including antigen presentation,
lymphocyte proliferation and traffic, secretion of cytokines
and antibodies, and shift of the T helper (Th)1 towards Th2
responses [20].
Skin Peripheral HPA Axis
The skin also developed a fully functional peripheral
HPA system where CRH, ACTH, and their receptors are
produced in skin cells [21, 22]. CRH is produced by
epidermal and hair follicle keratinocytes, melanocytes,
sebocytes, and mast cells upon stress, including immune
cytokines, UV irradiation, and cutaneous pathology [23, 24].
In human, CRH receptor (CRH-R) 1 was expressed in all
major cellular populations of epidermis, dermis, and subcutis
layers, while CRH-R2 was only expressed in hair follicle
keratinocytes and papilla fibroblasts [25, 26]. Human
melanocytes and dermal fibroblasts respond to CRH
signaling via the cAMP pathway, leading to ACTH and
corticosterone production [27, 28]. ACTH has also been
detected in keratinocytes, Langerhan cells, monocytes, and
macrophages [29].
The function of CRH in skin is very diverse and cell-type
specific. In epidermal keratinocytes, CRH inhibits
proliferation by arresting cells at the G0/1 cycle, and induces
differentiation by calcium influx and AP-1 transcription
pathway [30, 31]. MAPK pathway and VEGF down-
regulation was proposed to be a possible mechanism [32]. In
dermal fibroblasts and melanocytes CRH acts as growth
factor stimulating proliferation. It also inhibits apoptosis in
the same cells induced by starvation stress [33]. In mast
cells, CRH induces degranulation and increases vascular
permeability, demonstrating pro-inflammatory functions
[34]. It also leads to selective secretion of vascular
endothelial growth factor (VEGF) to promote angiogenesis
[35]. In keratinocytes, it stimulates the pro-inflammatory IL6
production [36]. However, in melanocytes CRH inhibits NF-
κB signaling, possibly to self-inhibit the inflammation
response [37]. In a human sebocyte model, CRH stimulates
lipid production through up-regulation of key lipogenesis
enzymes [38].
ACTH stimulates IL-18 production in skin keratinocytes.
IL-18 is a pro-inflammatory cytokine that enhances T-cell
activity and promotes T helper type 2 (Th2) cytokines
production [39]. Since CRH down-regulates IL-18 in
keratinocytes [40], IL-18 may participate in the negative
feedback loop to regulate HPA axis activity. In melanocytes
ACTH stimulates proliferation and melanogenesis with a
similar effect of α-MSH [41, 42]. Endogenous ACTH can
stimulate hair growth in mouse model [43]. In sebocytes,
ACTH can work through the MC5R receptor and induce
sebocytes differentiation [44].
SAM Axis
Stress also induces the release of catecholamines through
the sympathetic- adrenal medullary (SAM) axes. The inner
layer of the adrenal medulla releases epinephrine
(adrenaline) and norepinephrine (nonadrenaline) upon
activation by stress. They are the critical components of the
“fight or flight response”: acceleration of heart rate and
respiration, constriction of blood vessels except in the
muscles, increased perspiration, and dilation of pupil.
Epinephrine acts by binding to a variety of adrenergic
receptors, leading to decreased skin blood flow, and altered
immune and inflammation functions, including lymphocyte
trafficking, circulation, proliferation, and cytokine
production [45-47]. In monocytes and dendritic cells,
adrenergic signaling can inhibit IL-12 production via
increasing cAMP, thus blunting TH1 response and
promoting TH2 differentiation [48]. It also has an impact on
the production of various cytokines in dendritic cells [49].
The skin also holds a peripheral catecholamine system
where epinephrine is synthesized in keratinocytes while the
adrenergic receptors are present in both epidermal
keratinocytes and melanocytes [50]. In keratinocytes, after
epinephrine activates the β2-adrenoceptor, it induces a major
increase in cAMP, which in turn increases calcium
concentration through protein kinase C (PKC) activation [51,
52]. Since calcium level can regulate both epidermal
proliferation and differentiation, it is possible that
epinephrine can affect epidermal health. In melanocytes, the
epinepherine produced by surrounding keratinocytes can
promote melanogenesis [53]. Fibroblasts functions are also
impacted by epinephrine, including migration and collagen
production, both being important steps in wound healing
[54]. For a detailed review of epinephrine’s effect on wound
healing, please refer to the third section.
Neurotrophins, Substance P, and Prolactin
The skin is highly innervated so peripheral nerves can
also impact skin health through secreted factors like
neuropeptides (ex: substance P or SP) and neurotrophins
(NT). They serve as local stress responders that mediate
neurogenic inflammation [55]. NGF contributes to stress-
induced cutaneous hyperinnervation and affects all hallmarks
of allergic inflammation and cutaneous stress responsiveness
upstream of SP [56].
NGF (Nerve growth factor) is one of four NT family
members. It binds to the high affinity tyrosine kinase
receptor (TrkA, TrkB, and TrkC) and low affinity p75 NT
receptor, and promotes neurogenic inflammation by
stimulating cytokine releases from skin mast cells [57]. In
keratinocytes NGF promotes proliferation and protects cells
from UV-induced apoptosis [58-60]. In fibroblasts, NGF
induces proliferation, migration and differentiation into
myofibroblasts, which could play a vital role in cutaneous
wound healing [61]. In melanocytes, NGF receptors are
induced by UV irradiation and they can induce migration
and dendricity [62, 63]. In a stress-induced hair loss mouse
model, sonic stress induced rapid increase of NGF and p75
Brain-Skin Connection: Stress, Inflammation and Skin Aging Inflammation & Allergy - Drug Targets, 2014, Vol. 13, No. 3 179
NTR, which in turn significantly increased the number of
Substance P-positive sensory neurons, and eventually caused
premature hair growth termination [64].
Substance P (SP) is a stress-related pro-inflammatory
neuropeptide which is released from cutaneous peripheral
nerve terminals. During repeated sonic stress, SP+ nerve
fibers are significantly increased [64]. It is the key mediator
in connecting the brain to the hair follicle by stimulating
mast cells degranulation and increasing macrophage
infiltration. SP receptor antagonist can indeed normalize
stress-induced phenotypes [65]. Substance P participates in
the effect of CRH on mast cell degranulation during stress,
an important process in neuroinflammation [66]. It also
induces neutrophil and inflammatory cell infiltrates [67]. SP
can induce a variety of cytokines release from monocytes
Table 1. Major Stress Mediators in Skin
Stress Mediator
Source
Effector Cell
Functions in Skin
CRH
Hypothalamus;
Skin keratinocytes, sebacytes, and mast
cells
CRH-R1 is expressed in epidermis,
dermis and subcutis layer; CRH-R2 is
expressed in in hair follicle
keratinocytes and papilla fibroblasts
Stimulation of downstream ACTH and
cortisol production;
Proliferation, differentiation, apoptosis,
inflammation, and angiogenesis.
ACTH
Pituitary gland;
Skin melanocytes, epidermal and hair
follicle keratinocytes and dermal
fibroblasts; Langerhan cells, monocytes,
and macrophages
MC2-R is expressed in skin
melanocytes, hair follicles, epidermal
keratinocytes, sebaceous and eccrine
glands, as well as dermal fibroblasts,
sebaceous and eccrine glands, muscle
and dermal blood vessels
Stimulation of cortisol and
cortocosterone production;
Melanogenesis, cytokine production,
cell proliferation, dendritic formation,
hair growth, immune and inflammation
regulation.
Cortisol
Adrenal cortex;
Skin hair follicles, melanocytes, and
fibroblasts
glucocorticoids receptor (GR) is
ubiquitous expressed in all skin cells
Major impact on the immune and
inflammation system;
Cell proliferation and survival via the
PI3K/Akt pathway;
Hair follicle proliferation and
differentiation; Epidermal barrier
formation.
Neurotrophins
Central nervous system;
Skin sympathetic neurons, mast cells, T-
cells and B-cells, keratinocytes,
fibroblasts, and melanocytes
Two receptors TrK and p75 are
expressed in mast cells, immune cells,
keratinocytes, fibroblasts and
melanocytes
Promote skin innervations;
Promote survival and differentiation of
mast cells, and modify inflammatory
cytokines expressions;
Promote proliferation of keratinocytes;
Important for melanocytes migration,
viability and differentiation and protect
them from oxidative stress and
apoptosis;
Promote fibroblast differentiation and
migration, and possibly contraction and
MMP secretion.
Substance P
Sensory nerve fibers
Mast cells, macrophages, T-cells
Cytokine release to induce
inflammation, activate mast cells, and
induce lymphocyte proliferation
Induce vascular permeability.
Prolactin
Pituitary gland;
Skin hair follicle and epidermal
keratinocytes, fibroblasts, adipocytes,
sweat glands, and sebaceous glands
Prolactin receptor (PRLR) is ubiquitous
expressed except in fibroblasts
Autocrine hair growth modulator by
promoting catagen (hair regression);
Stimulate keratinocytes growth and
keratin production in keratinocytes;
Sebum production in sebaceous glands;
Immuno-modulation.
Catecholamines
(epinephrine and
norepinephrine)
Adrenal medulla;
Skin nerve fibers, keratinocytes
adrenergic receptors are expressed by
natural killer cells, monocytes, and T
cells, keratinocytes and melanocytes
Regulate keratinocytes proliferation,
differentiation, and migration;
Promote melanogenesis in melanocytes;
Decrease fibroblasts migration and
collagen secretion and impair wound
healing;
Suppress IL-12 in dendritic cells leading
to blunted Th1 and increased Th2
differentiation;
Important for lymphocyte trafficking,
circulation, proliferation, and cytokine
production.
180 Inflammation & Allergy - Drug Targets, 2014, Vol. 13, No. 3 Chen and Lyga
and T-cells, including IL-1, IL-6, and IL-12, leading to T-
cell proliferation and inflammation [68, 69]. Very
interestingly, SP can increase the virulence of multiple skin
microflora by increasing caspase and altering the actin
cytoskeleton. This could be another mechanism contributing
to its role in neurogenic inflammation [70].
Prolactin is the hormone best known for its function in
lactation and reproduction. It also has a global effect on body
weight and adipose tissue [71, 72]. It is also immediately
induced by psychological stress [73]. Recent research has
revealed its function and implication in the brain-skin
connection [74]. Prolactin stimulates keratinocytes
proliferation and regulates keratin expression in
keratinocytes [75, 76]. It stimulates sebum production in
sebaceous glands [77]. In human monocytes/macrophages,
prolactin stimulates heme oxygenase-1 production and
VEGF production, contributing to angiogenesis [78].
Prolactin was proposed to have immunoprotection functions
during stress because it can antagonize glucocorticoids
function and maintain survival and function of T
lymphocytes and macrophages [79, 80].
Mast Cells
Skin mast cells have emerged as a central player of the
skin stress responses. It was proposed as the “central
switchboards” of neurogenic inammation [81]. In skin they
Fig. (1). Central stress response and skin peripheral stress response.
Brain
Adrenal gland: secrete
GC and catecholamines
Hypothalamus:
secrete CRH
Pituitary gland:
secrete POMC
peptides including
ACTH
Brain: also secrete
NTs, SP, prolactin
Adrenal
Gland
Epidermal keratinocytes
and melanocytes: secrete
CRH, ACTH, NTs, prolactin,
and catecholamines
Dermal fibroblasts: secrete
ACTH, cortisol, NTs, and
prolactin
Skin Peripheral Stress Response
Blood vessels:
supply systematic
mediators and
Sebaceous gland:
produce CRH and
prolactin
Hair follicle: possess fully
Skin nerve endings:
secrete SP and
catecholamines
Mast cells: secrete CRH;
possess receptors for CRH,
cortisol, NTs, SP, and prolactin
Skin
Brain-Skin Connection: Stress, Inflammation and Skin Aging Inflammation & Allergy - Drug Targets, 2014, Vol. 13, No. 3 181
are located near SP+ nerve endings and blood vessels, where
they are the first-line defense of the innate immune system.
All the major stress pathways discussed above can affect
various aspects of mast cell functions, including survival,
activation, and downstream effectors secretion (See above
for details). These include various vasodilatory and
proinammatory mediators, ex: histamine, VEGF, cytokines,
nitric oxide (NO), and proteases. In turn, they serve as
central players in the skin neurogenic immune response
activated by stress.
SKIN NEUROGENIC INFLAMMATION DURING
STRESS RESPONSES
Stress is known to affect various diseases and conditions,
for example, asthma, arthritis, migraines, and multiple
sclerosis [82-85]. Specifically in skin, multiple
neuroinammatory conditions can be triggered or aggravated
by stress, such as: psoriasis, atopic dermatitis, acne, contact
dermatitis [86, 87], alopecia areata [88-91], itch or Pruritus
[92], and erythema. This section will only focus on several
skin conditions.
Psoriasis
Psoriasis is a chronic skin inammatory disease, affecting
about 2% of populations worldwide. It is characterized by
overproliferation of keratinocytes and inflammation, which lead
to epidermal hyperplasia, a hallmark of lesional psoriatic skin.
The psoriatic plaques are most seen over the elbows, knees and
scalp. Other pathological signatures include dysregulated
angiogenesis, skin infiltrating T lymphocyte, and expression of
proinammatory T helper (Th) 1 cytokines [93-95]. Although
recent research has revealed parts of the pathogenesis and the
intricate crosstalk between nerves, immune system, endocrine
system, and skin cells, there is still no cure for psoriasis.
Stress is both a consequence of living with psoriasis, and
a cause for psoriasis exacerbation [96, 97]. The pro-
inflammatory cytokines that are highly expressed in psoriasis
are potent activators of the HPA axis. This could lead to a
vicious cycle and amplify the negative effects [98]. Stress
leads to a hyporesponsive central HPA axis with blunted
cortisol response and upregulation of inflammatory
cytokines [99, 100]. In psoriasis stress also has an impact on
the skin peripheral HPA axis, and the SAM axis. However,
the exact role and mechanism still need to be elucidated by
further research due to conflicting data from different
research groups [101].
The role of NGF and substance P in psoriasis has been
extensively studied. It was discovered that psoriatic tissues
express high levels of NGF compared to the controls [102,
103]. NGF can contribute to keratinocytes proliferation [58,
59] and mast cell activation [57, 104], both being early
events of psoriatic lesion formation. NGF also contributes to
inflammation, by activating T lymphocytes [105] and
inducing chemokine expression from keratinocytes [106].
The critical role of NGF in psoriasis development is further
confirmed when blocker of TrkA, the high affinity NGF
receptor, can significantly improve transplanted psoriatic
plaques in a mouse model [107]. Substance P and SP-
positive cutaneous sensory nerves are both increased in
psoriasis skin [108, 109]. This could be downstream of NGF
signaling since NGF and its receptors play a crucial role in
regulating innervation and upregulating neuropeptides [110].
In fact, cutaneous denervation can improve inflammation
and reduce T-cell numbers, which is prevented by restoration
of SP signaling [111].
It was recently discovered that in keratinocytes prolactin
enhances interferon-gamma-induced production of (C-X-C
motif) ligand 9 (CXCL9), CXCL10, and CXCL11. Thus
prolactin may promote type 1 T cell infiltration into psoriatic
lesions via these chemokines [112]. It can also stimulate
keratinocytes proliferation [75], potentially promoting the
development of psoriatic plaques.
Acne
Acne vulgaris (or simply acne) is a very common skin
disease affecting a majority of the population at some point
in their life. It affects skin with the densest population of
sebaceous follicles, including the face, the upper part of the
chest, and the back. Acne pathogenesis is characterized by
increased colonization of P. acne anaerobic bacteria,
increased sebum production from the sebaceous glands,
inflammation, and hyper-keratinization [113].
Stress has long been suspected to induce acne flares by
clinical experiences and anecdotal observations [114, 115],
but it was only confirmed 10 years ago by a well controlled
study. In a student examination stress study, increased acne
severity is significantly associated with stress levels [116].
The role of skin peripheral HPA axis has been studied in
the pathogenesis of acne. CRH and its receptors have been
detected on sebocytes [23, 38]. It was shown that CRH
promotes lipogenesis in sebocytes through up-regulation of a
key enzyme [38]. In addition, it induces cytokines (IL-6 and
IL-11) productions in keratinocytes [36], contributing to
inflammation. ACTH and α-MSH also contribute to sebum
production and possibly worsen the acne phenotype [117,
118]. The role of neuropeptide, specifically substance P in
ance has been studied extensively [119]. Facial skin from
acne patients show marked increase of SP-positive nerve
fibers around the sebaceous glands and around acne lesions
[120]. SP can promote both proliferation and differentiation
of sebaceous glands [121]. SP induces gene expression of
PPAR-γ, which plays a unique role in stimulating sebocyte
lipogenesis. It also stimulates various pro-inflammatory
cytokines release from sebocytes, including IL-1, IL-6, and
TNF-α [122]. In addition, SP can activate mast cells, adding
another player to the neurogenic inflammation [66].
Atopic Dermatitis
Atopic dermatitis or AD, is a chronic and relapsing
inflammatory skin disease often associated with eczema and
itch [123]. A complex interaction of genetic, environmental,
and immunological factors is manifested in AD. Skin barrier
function defect is a key feature of AD because null mutations
in the filaggrin gene are an important predisposing factor for
AD. Filaggrin protein is essential for the final cell
compacting process to form the terminally differentiated
stratum corneum [124-126]. Environmental factors such as
allergens or microbial organisms are critical triggers or
complications in the disease [127]. And Toll-like receptor 2
182 Inflammation & Allergy - Drug Targets, 2014, Vol. 13, No. 3 Chen and Lyga
(TLR-2) has emerged as another important player. It
recognizes cell wall components of bacteria and its gene
polymorphism has been associated with AD [128]. AD is
also characterized by an acute phase with predominant TH2
response (IL-4, IL-13, and IL-31) and a chronic phase
towards a TH1 (IL-5, IL-12, and IFN-γ) feature [129].
Similar to psoriasis, AD symptoms and psychological
stress seem to form a vicious cycle. AD patients have been
reported to have anxiety and depression, while psychological
stress in turn can exacerbate AD pathology [130-132].
Stress can impact AD symptoms through different
mechanisms. First of all, stress can negatively affect skin’s
permeability barrier function and homeostasis. In AD
patients, barrier dysfunction could lead to increased
sensitization to allergens and microbial organisms, increased
transepidermal water loss, and lowered threshold for itch
[133]. For a detailed review of how stress impact barrier
function, please refer to the next section.
Stress also contributes to the immune and inflammation
dysfunction in AD patients. HPA response after stress was
found to be impaired in AD patients. This
hyporesponsiveness was linked to severity of inflammation
[134]. The blunted HPA response was proposed to lead to
immune function dysregulation, allergic inflammation, and
exacerbation of disease [135]. On the other hand, the SAM
axis is over-reactive. Both basal and stress-induced levels of
catecholamines are higher in AD patients compared to
control [134]. However, the adrenergic receptor mutation or
polymorphisms have been discovered in AD. A point
mutation in the β2-adrenoceptor gene could alter the
structure and function of the receptor, thereby leading to a
low density of receptors on both keratinocytes and peripheral
blood lymphocytes [136]. Receptor mutation or
polymorphism is also associated with AD [13, 136]. So the
catecholamines signaling is probably still dysfunctional even
with upregulated ligand. It was discovered that adrenoceptor
signaling defect with TLR activation can shift the recall
memory response to the Th1 type, releasing multiple
cytokines. This could be a mechanism where SAM axis can
contribute to chronic AD pathogenesis [137]. Further
research is warranted to elucidate the role of SAM axis in
AD pathogenesis.
In a mouse model for atopic dermatitis, it was discovered
that stress increased cutaneous but not serum or
hypothalamic NGF. Treatment with NGF neutralizing
antibody can partially recover the skin inflammation
phenotype by reducing epidermal thickening, decreasing pro-
inflammatory cytokines induction, and attenuating allergy-
characteristic cellular infiltration [138]. However, there are
conflicting data on NGF expression in AD patients. Some
research showed increased NGF [132, 139-141], while
others demonstrated no significant difference or even
decreased NGF level [142, 143]. Further research is needed
in this area to elucidate the differences. Substance P was also
involved in the neurogenic inflammation that worsens
dermatitis because the exacerbation was not seen in mice
lacking the SP receptor [144]. It was shown that SP receptor
expression is much higher in AD patients’ peripheral blood
mononuclear cells (PBMCs) than in healthy control. SP can
increase PBMCs proliferation rate and TNF-α and IL-10
production [12]. However, in an atopic dermatitis mouse
model, the SP+ nerve fibers in skin are decreased in stressed
animals [145]. The exact role of SP in AD remains to be
clarified. Mast cells also play a role in AD neurogenic
inflammation. Mast cell numbers are increased in lesional
AD skin, as well as mast cell-nerve contacts [146, 147].
Recently it was discovered that oxytocin (OXT), a
neuropeptide playing a major role in behavior regulation, is
down-regulated in lesional AD skin. Both oxytocin and its
receptor are detected in keratinocytes and fibroblasts, and it
affects cell proliferation, inammatory cytokines release and
oxidative stress responses [148].
IMPACT OF STRESS ON SKIN BARRIER FUNCTION
AND WOUND HEALING
The stratum corneum (SC) plays important barrier
functions by regulating epidermal permeability and
homeostasis. This protein/lipid barrier creates a surface seal
essential for maintenance of hydration and protection against
microbial infection. Disruption of the skin barrier function
can lead to flaky or dry skin [127]. Alternation of the lipids
composition has also been linked to skin diseases like atopic
dermatisis and psoriasis [149, 150].
Stress can cause detrimental physiological and functional
consequences in the skin. Overcrowding stress in mice
caused higher transepidermal water loss, lower water
retention property and impaired barrier function, leading to
moderate exfoliation and slight wrinkle formation. The exact
mechanism is still unclear, but a decrease in ceramide and
pyrrolidone carboxylic acid was observed [151, 152]. Other
studies have corroborated the result and further confirmed
the involvement of stress by demonstrating that treatment of
glucocorticoid receptor antagonist or CRH receptor
antagonist can block the adverse events [153, 154]. A study
using topical glucocorticoid-treated mice proposed that lipid
synthesis inhibition is key for the stress-induced
abnormalities [155]. In a later insomnia study, the authors
discovered that stress can significantly impair epidermal
proliferation and differentiation, decrease size and density of
corneodesmosomes, and decrease lipid synthesis and
lamellar body production. It also confirmed the critical role
of lipids because topical application of physiological lipids
including ceramides and free fatty acids can restore barrier
homeostasis and stratum corneum integrity [156].
Similar effects were also observed in human subjects. For
example, final exam stress on students caused a decline in
permeability barrier recovery kinetics [157]. Interview stress
caused barrier function recovery delay, increased plasma
cortisol level, and activated several inflammation and
immune players, including interleukin-1β, interleukin-10,
tumor necrosis factor α, and circulating natural killer cells
[158]. Stress due to marital disruption significantly delayed
skin barrier recovery after tape stripping [159].
One of skin’s major functions is physical protection and
wound repair upon injury. Wound healing is an intricate
process that involves resident skin cells, skin extracellular
matrix and systematic factors. Mechanosensing and
mechanotransduction also play vital roles in wound closure
[160]. It is divided into three major yet overlapping phases:
inflammation, proliferation, and remodeling. During
inflammation, cytokines and chemokines including IL-1α,
Brain-Skin Connection: Stress, Inflammation and Skin Aging Inflammation & Allergy - Drug Targets, 2014, Vol. 13, No. 3 183
IL-1β, IL8, transforming growth factor-β, vascular
endothelial growth factor (VEGF), and tumor necrosis factor
alpha (TNF-α) play important roles. They protect against
infection, attract phagocytes, and recruit fibroblasts. In
proliferation, new granulation tissue is rebuilt with collagen,
blood vessel, and other ECM proteins. Finally, in remodeling
collagen is remodeled and realigned and apoptosis remove
unnecessary cells, which may take weeks or months [161].
An extensive literature search has revealed that chronic
systemic corticosteroids have a negative impact on all three
phases of wound healing [162]. A meta-analysis also
concluded that stress was associated with impaired healing
or dysregulation of healing biomarkers [163].
The negative impact of stress on wound healing was first
observed clinically in human when caregivers of demented
relatives needs 20% more time for complete dermal wound
healing [164]. Anxiety and depression are also associated
with delayed healing in chronic wounds [165]. It was found
that perceived stress and elevated cortisol level are among
the contributing factors [166].
Subsequent mouse and human studies have revealed
some important molecular mechanisms. The HPA axis plays
a vital role because glucocorticoid receptor antagonist
treatment can restore proper healing rate [19]. Inflammatory
markers (including IL1α and IL1β) kinetics are disrupted
[167]. Two key cytokines (IL1α and IL8) were found to be
significantly lower at wound site in stressed patients [168].
MMP2 expression in blister wound was found to be
negatively correlated with plasma cortisol level [169].
Rotational stress in mice can delay wound closure by
delaying immune cell infiltration, lowering TNF-α level at
wound site, and reducing MMP activity [170]. Bacterial
infections during early stages of wound healing are also
more prominent due to compromised skin immune function
[171]. Antimicrobial peptide expression was also decreased
by stress leading to increased severity of infection at wound
site [172]. Furthermore, myofibroblasts differentiation is
delayed, leading to severely impaired wound contraction
[173]. TGF-β signaling could also be involved since it was
shown that endogenous glucocorticoids plays an important
part in wound healing by altering TGF-β expression which
affects fibroblast proliferation, migration, and differentiation
[174, 175].
Alternatively, stress can also work through the SAM -
epinephrine pathway to negatively impact keratinocyte
motility and wound re-epithelialization. Epinephrine can be
induced by stress systematically and can also be produced
locally by wound site. Epinephrine binds to the β2-
adrenergic receptor (β2AR) in keratinocytes, and decreases
downstream PI3K/AKT signaling. This leads to stabilization
of actin cytoskeleton and increased focal adhesion formation,
both inhibiting migration and proper wound healing. β2AR
antagonist was shown to be effective at reversing this
impairment [176]. Antagonist can also accelerate skin barrier
recovery and reduce epidermal hyperplasia [177].
Epinephrine was found to decrease fibroblast migration and
MMP2 secretion in vitro [170]. It can also reduce collagen
deposition by fibroblasts [54]. A recent research discovered
that neutrophil trafficking alternation and IL-6 up-regulation
were induced by epinephrine and inflammatory responses are
impaired in wound healing [178]. Stress activated SAM
pathway can alter blood flow. Peripheral vasoconstriction
can limit the blood and oxygen supply at the wounding site,
which limit the rate of healing by increasing the production
of nitrix oxide (NO). Hyperbaric oxygen therapy was shown
to effectively correct stress-impaired wound healing in
mouse [179]. In human, emotional disclosure intervention
was shown to significantly improve wound healing after skin
biopsy [180].
LONG TERM SKIN DAMAGE OF CHRONIC STRESS
Under short term acute stress, the HPA axis is tightly
regulated through feedback mechanisms. Increased cortisol
level can keep the HPA activity in check through both a slow
genomic and a fast non-genomic negative feedback
mechanism [181]. Acute stress can induce a significant re-
distribution of lymphocytes from the blood to the skin,
leading to enhanced skin immunity and successful stress
adaptation [182]. In a mouse restraint stress study, both
innate and adaptive immunity are involved: dendritic cells
mature and traffick from skin to the lymph nodes,
macrophages are activated, and surveillance T cells are
recruited to the skin [183]. Acute stress also suppresses ROS
production [184].
In contrast to acute stress, which may augment innate and
adaptive immune responses, chronic stress usually
suppresses immunoprotection, increases susceptibility to
infections, and exacerbates some allergic and inflammatory
diseases [185]. This is due to altered stress responses after
repeated or prolonged stress termed stress habituation, which
reduces HPA axis activation, but also sensitizes reactivity to
new stimuli [186]. Aging also has a negative effect on the
feedback system, as shown in both rats and human [187,
188].
In a mouse study, chronic stress induced by fox urine can
significantly accelerate UV-induced skin neoplasma
development. Stressed group starts to develop skin tumor
much earlier than the control group and the survival rate is
significantly lower [189]. It was later discovered that chronic
stress caused a significant decrease in T-cell infiltration in
the skin and cell-mediated immunity was greatly
compromised. Several important skin immune markers are
decreased by stress, including IL12 (Th-1 response
promotion and cellular immunity mediator), IFN-γ (tumor
recognition and elimination), and CCL27 (skin homing T-
cell attraction) [190].
Skin aging is characterized by formation of lines and
wrinkles, increased pigmentation, loss of elasticity and
firmness, and dull skin. It is a consequence of both intrinsic
factors and extrinsic factors. There are two major theories for
aging: the programmatic theory which focuses on reduced
cellular life span, decreased responsiveness and
functionality, and dysfunctional immune responses; while
the stochastic theory points towards environmental damages,
focusing on DNA damage, inflammation and free radical
formation [191-193].
The exact mechanism of how stress impacts skin aging is
still quite elusive. However, recent research has provided
evidence of possible pathways that might contribute to skin
aging [194]. UV irradiation is one of the major extrinsic
stressors responsible for premature skin aging, thus the term
184 Inflammation & Allergy - Drug Targets, 2014, Vol. 13, No. 3 Chen and Lyga
“photoaging”. UV irradiation is one of the major stimulants
of skin HPA axis. It induces expression of CRH, POMC
peptides, ACTH, cortisol, and β-endorphin [195].
Considering that skin is under daily UV stress, the repeated
activation of the HPA axis can have detrimental effects on
the skin. Long term glucocorticoids (GC) therapy for treating
skin inflammatory disease has severe skin atrophy side
effect, including decreased epidermal thickness, flat dermal-
epidermal junction, reduced number of fibroblasts, and
disruption of the dermal fibrous network, which are also
hallmarks of skin aging. Several extracellular matrix proteins
are negatively impacted by GC, including collagen I,
collagen III, proteoglycans, and elastin [196].
Epinephrine, norepinephrine and cortisol were found to
increase DNA damage, interfere with DNA repair, and alter
transcriptional regulation of the cell cycle [197]. It has been
demonstrated that stress can induce DNA damage through
the β2-adrenoreceptor (β2AR) pathway. Chronic
catecholamine stimulation leads to p53 degradation and
accumulation of DNA damage [198]. Furthermore, blockage
of the β2AR pathway can prevent DNA damage
accumulation [199]. Thus, stress-induced SAM axis can also
contribute to skin aging by compromising genome integrity.
Reactive oxygen species (ROS) was recently discovered
to also play a role in the stress-SP-mast cell pathway. In
chronic restraint stress mice, oxidative stress pathway has
two-way crosstalks with the SP pathway and antioxidantant
Tempol was shown to be also effective at normalizing hair
growth [200]. Repeated short term stress can induce ROS
production by up-regulation of NF-κB in the skin induced by
toxicant and UVB. Stress augmenting depletion of cellular
anti-oxidant machinery is shown by significant loss of GSH
(Glutathione and GSH dependant enzymes), superoxide
dismutase and catalase activity [201]. It was also discovered
that in the brain, stress leads to increased oxidative stress and
mitochondria dysfunction [202, 203]. Considering ROS
production in the mitochondria is the major determinant of
aging and life span [204], stress can have a major impact on
skin aging through the ROS pathway.
Smoking and air pollution have been confirmed as
critical chronic stressors that impact skin aging significantly.
In photoprotected area, years of smoking and packs smoked
per day are strong indicators of premature skin aging [205].
In an identical twin study, it was observed that 5-year
difference in smoking history led to noticeable changes in
skin aging [134]. Significant increase in temperature and
decrease in oxygen content were observed in skin after
smoking [69]. ROS production and arylhydrocarbon receptor
(AhR) signaling pathway lead to dermal matrix breakdown
and wrinkle formation [206]. Air born particles exposure
from traffic was associated with significant increase in
pigment spots and facial wrinkles [207]. ROS production is
the major underlying mechanism. It can induce Vitamin E
depletion and lipid peroxidation, as well as MMP induction
[208, 209]. Direct mitochondria damage, and AhR pathway
have also been proposed as possible mechanisms [210-212].
Recently, telomere shortening has emerged as another
possible cellular mechanism linking chronic psychological
stress and aging. Telomeres are DNA repeats at the ends of
chromosomes and it shortens with each cell division,
eventually leading to replicative senescence and premature
cellular aging. Various chronic stress situations have been
associated with shorter telomere length, including caregiving
for sick child with chronic conditions or elderly dementia
patients, major depression, childhood adversity, and
exposure to intimate partner violence [120, 122, 140, 213].
Although the exact mechanism of how stress induces
telomere shortening is still under debate, cortisol and
epigenetic modulation have been proposed as possible routes
[119, 214]. Telomere shortening can lead to the
downregulation of mitochondria biogenesis and ROS
production [113, 215]. This could constitute a vicious cycle
where stress from lifestyle or habits further exacerbate the
skin damage and signs of aging.
A recent study established the negative effect of sleep
deprivation on skin aging [121]. It was found that poor
quality sleepers showed increased signs of intrinsic skin
aging including fine lines, uneven pigmentation and reduced
elasticity. They also recover much slower after skin barrier
disruption. Hypoxia stress induced during wound healing can
also impact skin aging by disrupting basement membrane
involving laminin and integrins [216].
CONCLUSION AND FUTURE PERSPECTIVES
In recent years, emerging research has demonstrated that
skin is not only a target of psychological stress signaling
modulation, it also actively participates in the stress response
by a local HPA axis, peripheral nerve endings, and local skin
cells including keratinocytes, mast cells, and immune cells.
There are also feedback mechanisms and crosstalk between
the brain and the skin, and pro-inflammatory cytokines and
neurogenic inflammatory pathways play huge roles in
mediating such responses. In this review, we summarized
findings that shed light on how the “brain-skin connection”
actually works: what are the major pathways and effector
cells; how they negatively affect skin functions and diseases;
and how chronic stress can have a detrimental effect on skin
aging.
As of today there is no proven medical treatment that can
either prevent or treat stress-induced or exacerbated skin
conditions or skin aging. Several key players have been
proposed which might give rise to potential therapeutics.
Skin mast cells are activated by stress, and in turn they also
produce stress hormones and inflammatory factors. This
could lead to a vicious cycle of stress-induced inflammatory
events. Indeed mast cells have been implicated in numerous
skin diseases including acne, atopic dermatitis, psoriasis and
pruritus [217]. Several compounds have been found to be
effective in inhibiting cytokine release from mast cells [128].
Dietary supplements combining active flavonoids with
proteoglycans could also be helpful in atopic and
inflammatory conditions [146]. Specific receptor antagonists
against CRH receptors, NGF receptors, or SP receptors could
also prove to be effective in relieving stress-induced
neurogenic inflammation [218].
In the future, researches should further investigate the
HPA axis, proinflammatory hormones and cytokines, and
their downstream effectors that mediate the brain-skin
connection. Future researches can look into the ways to
modulate this connection and discover novel therapeutics for
skin diseases and anti-aging treatments.
Brain-Skin Connection: Stress, Inflammation and Skin Aging Inflammation & Allergy - Drug Targets, 2014, Vol. 13, No. 3 185
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
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Received: January 6, 2014 Revised: May 7, 2014 Accepted: May 20, 2014
... The skin is a sensory organ, sending and receiving signals to and from the brain. This bidirectional relationship is mediated by signaling molecules [12]. Under stressful conditions, cellular proliferation and differentiation is impaired, decreasing lipid synthesis and barrier function and dysregulating healing biomarkers [12]. ...
... This bidirectional relationship is mediated by signaling molecules [12]. Under stressful conditions, cellular proliferation and differentiation is impaired, decreasing lipid synthesis and barrier function and dysregulating healing biomarkers [12]. An integral mediator of the skin-brain axis is the transient receptor potential vanilloid 1 (TRPV1) receptor, a temperature-sensitive calcium channel [13]. ...
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... Additionally, their impact on the clinical outcomes of vitiligo treatment has not been explored sufficiently. Studies have indicated that mental health disorders can induce and worsen skin conditions, such as psoriasis and atopic dermatitis, via the brain-skin axis (Marek-Jozefowicz et al., 2022;Chen and Lyga, 2014). Vitiligo patients exhibit a higher incidence of stressful life events prior to the onset of their condition (Picardi et al., 2003). ...
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... SP also stimulates basophils expressing NK-1R, leading to stronger inflammatory responses [87]. Furthermore, SP is a key mediator in neurogenic inflammation, linking the nervous system and immune response in the skin [89], and might act as a trigger in CU [90,91]. The ability of SP to activate MCs is concentration dependent [92]. ...
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... Elevated glucocorticoids can increase the expression of pro-inflammatory genes (e.g., iNOS, IL-1β, TNF-α) and decrease the expression of anti-inflammatory genes including IL-1ra, IL-10, and MKP-1, also leading to telomeres shortening [49]. Additionally, the production of glucocorticoids, ROS, and inflammatory markers would destroy collagen and elastin in the skin, accelerating wrinkling and sagging and leading to facial aging [52]. Interestingly, it is reported that the alternations of HPA axis induced by stress actions after traumatic events [53] or psychopathology (e.g., depression [54] and anxiety [55]) are possibly reversible, which explains our findings of no accelerated aging among participants with childhood adversities but who maintained good psychological conditions. ...
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Often psychiatric co-morbidity has been observed in dermatology patients. Apart from regular dermatologic therapy employed in treating them; certain psychiatric drugs, along with other non-pharmacological measures, if combined in managing these patients, would certainly yield superior results. This comprehensive review throws light on various psychiatric drugs along with other adjuvant treatment modalities that could serve as a ready reckoner to skin specialists while encountering patients who apart from having cutaneous problems, also manifest with an associated psychological component that may need scrupulous evaluation in order to obtain a proper solution.
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