Clinics in Dermatology (2012) 30, 263–268

Regulation of permeability barrier homeostasis

Kenneth R. Feingold, MD a,⁎, Mitsuhiro Denda, PhD b
a
Metabolism Section, Department of Veterans Affairs Medical Center, University of California at San Francisco,
School of Medicine, 4150 Clement St, San Francisco, CA 94121, USA
b
Shiseido Innovative Science Research and Development Center, Kanazawa-ku, Yokohama 236-8643, Japan

Abstract A major function of the skin is to provide a barrier to the movement of water and electrolytes,
which is required for life in a terrestrial environment. This permeability barrier is localized to the stratum
corneum and is mediated by extracellular lipid-enriched lamellar membranes, which are delivered to the
extracellular spaces by the secretion of lamellar bodies by stratum granulosum cells. A large number of
factors have been shown to regulate the formation of this permeability barrier. Specifically, lamellar
body secretion and permeability barrier formation are accelerated by decreases in the calcium content in
the stratum granulosum layer of the epidermis. In addition, increased expression of cytokines and
growth factors and the activation of nuclear hormone receptors (peroxisome proliferator-activated
receptors, liver X receptors, vitamin D receptor) accelerate permeability barrier formation. In contrast,
nitric oxide, protease-activated receptor 2 activation, glucocorticoids, and testosterone inhibit
permeability barrier formation. The ability of a variety of factors to regulate permeability barrier
formation allows for a more precise and nuanced regulation.
Published by Elsevier Inc.

Introduction scaffold for the extracellular lamellar membranes, and

A major function of the skin is to provide a barrier to the
movement of water and electrolytes. 1 Without this perme-
ability barrier, life in a terrestrial environment would be
impossible. When this permeability barrier is dysfunctional,
such as in patients with severe burns or premature infants,
there is a marked loss of fluid and electrolytes that leads to
great morbidity and even death. Less severe abnormalities in
permeability barrier function occur in neonates, the elderly,
and in patients with a variety of cutaneous diseases, such as
atopic dermatitis and psoriasis.
This permeability barrier resides in the stratum corneum,
the outermost layer of the epidermis, and is mediated by
extracellular neutral lipid enriched lamellar membranes that
surround the corneocytes. 1,2 The corneocytes provide not
only for the mechanical strength of the skin but also a
⁎ Corresponding author. Tel.: +1 415 750 2005; fax: +1 415 750 6927.
E-mail address: kenneth.feingold@ucsf.edu (K.R. Feingold).
abnormalities in corneocytes can lead to permeability barrier
abnormalities. 3,4 The extracellular lipids that mediate
permeability barrier function in the stratum corneum have
a unique composition and are very different from the lipids
that constitute most biologic membranes. 2 Of the total lipid
mass, approximately 25% is cholesterol, 50% is ceramides,
and 15% is free fatty acids. Very little phospholipid is
present. These lipids are delivered to the extracellular spaces
of the stratum corneum when the stratum granulosum cells
secrete lamellar bodies, ovoid organelles that form during
keratinocyte differentiation. 1,2
To understand how the formation of the permeability
barrier occurs and the factors that regulate this formation, our
group has acutely perturbed permeability function in hairless
mice and then determined the response. 2,5,6 We have used a
variety of techniques to acutely perturb permeability barrier
function, including mechanically removing the stratum
corneum by tape stripping or by extracting the extracellular
stratum corneum lipids with acetone (a solvent) or sodium
dodecyl sulfate (a detergent). 6 After permeability barrier

0738-081X/$ – see front matter. Published by Elsevier Inc.

doi:10.1016/j.clindermatol.2011.08.008
264
disruption, there are marked alterations in the underlying
viable epidermis that result in the rapid restoration of
permeability barrier function toward normal. 2 By 6 hours
after acute barrier disruption, greater than 50% of perme-
ability barrier function is restored in mice. 2,5,6 The rate of
recovery is faster when the degree of barrier disruption is
greater. 5 Permeability barrier function in humans is also
rapidly restored toward normal after acute barrier disruption,
but the rate of recovery is slower than in mice. 7 The
metabolic response in humans to permeability barrier
disruption is also very similar to what is observed in mice.
Metabolic changes in the epidermis that
restore permeability barrier function
To rapidly restore permeability barrier function toward
normal after acute barrier disruption requires a multitude
of changes in the underlying epidermis. 2 Within 15
minutes after acute barrier disruption, the upper stratum
granulosum cells secrete a large percentage of their stored
lamellar bodies, so that only a small number of lamellar
bodies remain in the cytoplasm of these cells. 2 The
stratum granulosum cells begin to rapidly synthesize new
lamellar bodies and continue to secrete these newly formed
lamellar bodies.
Simultaneous with the formation of these new lamellar
bodies is an increase in messenger RNA levels and activity of
key enzymes such as 3-hydoxy-3-methyl-glutary-coenzyme
A (HMG-CoA) reductase, squalene synthase, acetyl-coen-
zyme A carboxylase, fatty acid synthase, and serine
palmitoyl transferase, resulting in an increase in cholesterol,
fatty acid, and ceramide synthesis above their already high
basal levels in the epidermis. 2 In addition to an increase in
the mass of HMG-CoA reductase, the catalytic activity of
this enzyme also increases due to a change in phosphory-
lation state. Inhibition of cholesterol, fatty acid, or ceramide
synthesis blocks the formation of new lamellar bodies and
permeability barrier recovery is delayed, indicating that this
increase in de novo synthesis of lipids is required for new
lamellar body formation. 2
In addition to de novo lipid synthesis, extraepidermal
lipids also are a source of lipids for lamellar body formation.
After permeability barrier disruption, there is an increase in
the receptors that mediate the uptake of lipoproteins (low-
density lipoprotein receptor and scavenger receptor class B
member 1) and the transporters that facilitate the entry of
fatty acids into cells, including fatty acid transport protein 1
(FATP-1), FATP-6, and cluster of differentiation (CD) 36. 2
In addition, adenosine triphosphate (ATP)-binding cassette
transporter 1 (ABCA1), a transporter that effluxes choles-
terol and phospholipids from cells to high-density lipopro-
tein, is decreased after permeability barrier disruption, which
would increase the amount of lipid available for lamellar
body synthesis. 8
K.R. Feingold, M. Denda
The lipids secreted by stratum granulosum cells must be
processed in the extracellular space of the stratum corneum
for the formation of mature functional lamellar membranes
that impede water and electrolyte movement. 2 Lamellar
bodies secrete lipid into the extracellular spaces of the
stratum corneum and also specific enzymes involved in the
extracellular processing of lipids. Specifically, glucosylcer-
amides must be metabolized to ceramides, a reaction
catalyzed by β-glucocerebrosidase; sphingomyelins must
be converted to ceramides, a reaction catalyzed by acid
sphingomyelinase; and phospholipids must be catabolized
to free fatty acids, a reaction catalyzed by secreted
phospholipases A2. 2 After acute permeability barrier
disruption, there is an increase in the activity and
expression of β-glucocerebrosidase and acid sphingomye-
linase, which would facilitate the formation of mature
functional lamellar membranes. 2
Role of calcium in the homeostatic
repair response
In the epidermis, there is calcium gradient, with high
concentrations of calcium observed in the upper epidermis
(stratum granulosum) and low concentrations of calcium
observed in the lower epidermis (basal layer). 9 Immedi-
ately after acute barrier disruption, the increased water
movement through the defective stratum corneum carries
calcium outward, resulting in loss of the calcium gradient,
with a marked decrease in the calcium localized to the
upper epidermis. 10,11 Maintaining a high calcium concen-
tration in the upper epidermis after barrier disruption by
immersing the skin in a high calcium solution blocks
lamellar body secretion and inhibits normal permeability
barrier repair. 10-12 If the calcium content in the upper
epidermis is lowered by iontophoresis or sonophoresis,
without disrupting the permeability barrier, lamellar body
secretion is stimulated. 13,14 These results indicate that
calcium levels in the upper epidermis are a key signal that
regulates lamellar body secretion. Parallel changes in other
ions, such as potassium, are also important regulators of
lamellar body secretion and permeability barrier repair. 10,15
The calcium inhibition of permeability barrier repair can
be blocked by verapamil and nifedipine, which block
calcium transport into cells by the L-channel. 10 Calmodulin
inhibitors, trifluoroperazine, or N-6-aminohexyl-5-chloro-1-
naphthalenesulfonamide, also reduced the ability of exoge-
nous calcium to inhibit permeability barrier recovery. 10 The
precise pathways and mechanisms by which increased levels
of intracellular calcium inhibit lamellar body secretion by
keratinocytes remain to be elucidated, however.
Although these studies show that decreases in calcium
in the outer epidermis signal lamellar body secretion and
permeability barrier repair, the increased concentrations
of calcium in the outer epidermis depend on normal
Regulation of permeability barrier homeostasis
permeability barrier function. The restoration of the
calcium gradient after acute permeability barrier disruption
closely parallels the normalization of permeability barrier
function. 16,17 Delaying or accelerating the restoration of
the permeability barrier function also accelerates or delays
the formation of the calcium gradient. 16,17 In a similar
fashion, the appearance of the calcium gradient during
fetal development occurs simultaneously with the forma-
tion of the permeability barrier. 18 Accelerating or delaying
permeable barrier formation in the fetus also affects the
development of the calcium gradient. 18 Together these
observations indicate that the formation of the calcium
gradient in the epidermis depends on normal permeability
barrier function. Because a large portion of the calcium in
the epidermis is localized intracellularly in organelles
such as the endoplasmic reticulum and Golgi, it is likely
that other factors also influence calcium localization in
the epidermis.
Role of other signaling pathways in stimulating
the homeostatic repair response
Keratinocytes produce a wide array of cytokines,
including tumor necrosis factor and interleukin 1α (IL-1α),
IL-1β, and IL-6. Disruption of the permeability barrier also
increases the expression of these cytokines. 19,20. Studies in
mice deficient in these cytokines or their receptors have
shown delays in permeability barrier recovery after acute
disruption, suggesting that the increased cytokine production
facilitates barrier repair. 21,22 Cytokines are well known to
stimulate lipid synthesis and metabolism, and one could
anticipate that an increase in epidermal lipids induced by
cytokines could facilitate lamellar body formation and
permeability barrier recovery. 21,23,24
In addition to cytokines, growth factors are also likely
involved in regulating permeability barrier repair. After
acute disruption of the permeability barrier, there is an
increase in the expression of growth factors, such as
vascular endothelial growth factor (VEGF), nerve growth
factor, and amphiregulin, whereas transforming growth
factor-α does not change and transforming growth factor-β
decreases. 25,26 Recent studies have shown that permeability
barrier repair is delayed in VEGF-deficient mice, indicating
that this growth factor is important in facilitating perme-
ability barrier repair. 25
Peroxisome proliferator-activated receptor-α (PPAR-α),
PPAR-β/δ, PPAR-γ, and liver X receptor-α (LXR-α) and
LXR-β, are expressed in cultured human keratinocytes and
murine epidermis. 27 Activation of PPARs by fatty acids and
exogenous ligands such as clofibrate and LXRs by
oxysterols and exogenous ligands, such as TO901317,
regulate the expression of many important aspects of
keratinocyte metabolism. 27 Activation of PPARs and
LXRs stimulate involucrin and loricrin expression, key
265
corneocyte envelope proteins, and increase the expression of
transglutaminase 1, a crucial enzyme for the cross-linking of
cornified envelope proteins. 27 Activation of PPARs and
LXRs also stimulates permeability barrier recovery after
acute barrier disruption. 27,28 Studies have further shown that
PPAR and LXR activation stimulates epidermal lipid
synthesis, increases ABCA12 expression, accelerates lamel-
lar body secretion, and increases the activity of the enzymes
required for the extracellular processing of lipid, which
together likely accounts for the improvement in permeability
barrier homeostasis. 27-29 Of note in PPAR- β/δ–deficient
mice, recovery of permeability barrier recovery is delayed,
indicating that this receptor plays a physiologic role in
mediating permeability barrier homeostasis. 30
Vitamin D and the vitamin D receptor also regulate
permeability barrier formation. Mice deficient in 25 hydro-
xyvitamin D1 α-hydoxylase, which is required for the
formation of active 1, 25 dihydroxyvitamin D, have normal
basal permeability barrier function but impaired barrier
repair after acute disruption due to a decrease in lamellar
body secretion. 31 Mice deficient in the vitamin D receptor
also have defects in permeability barrier homeostasis due to a
decrease in the number of lamellar bodies. 32 Thus, the
activation of a number of different nuclear hormone
receptors (PPARs, LXR, and vitamin D receptor) is involved
in regulating lamellar body formation and secretion and
permeability barrier homeostasis.
Keratinocytes express many of the same receptors that
are expressed in neurons, including histamine (H1 and H2),
γ-aminobutyric (type A), β-2-adrenergic, glycine, glutamate
(N-methyl D-aspartate type), dopamine (D2), transient
receptor potential channels (TRP) V1, TRPV4, TRPA1,
and TRPM8, and nicotinic acetylcholine receptors. Studies
have shown that stimulating or inhibiting these receptors
with exogenous ligands can accelerate or inhibit perme-
ability barrier repair. 33-42 At this time, it is unknown
whether the production of the ligands for these receptors is
altered by permeability barrier disruption and whether these
pathways play a physiologic role in regulating permeability
barrier repair.
Role of signaling pathways in inhibiting the
homeostatic repair response
Studies have demonstrated an important role of nitric
oxide in inhibiting permeability barrier repair. 43-45 They
demonstrated that:
• Permeability barrier disruption enhanced nitric oxide
production and could be blocked by a neuronal nitric
oxide synthase (nNOS) inhibitor, but not by an
inducible nitric oxide synthase (iNOS) inhibitor.
• Topical application of an nNOS but not an iNOS
inhibitor accelerated permeability barrier recovery.
266
• Permeability barrier recovery was also accelerated in
nNOS-deficient mice but not in iNOS-deficient mice.
• Endothelial nitric oxide synthase (eNOS)-deficient
mice also have a faster recovery of permeability barrier
function after acute disruption.
Together these results demonstrate that increased nitric
oxide production delays permeability barrier repair.
Studies have also demonstrated that proteinase-activated
receptor 2 (PAR2) is involved in delaying permeability
barrier repair. 46 PAR2 is activated by trypticlike serine
proteases, and after permeability barrier disruption, there is
an increase in serine protease activity. 46,47 The basis for this
increase in serine protease activity is related to changes in
stratum corneum pH. 48,49 Under usual circumstances, the
pH of the stratum corneum is acidic (pH 5.0-5.5), but the pH
increases after permeability barrier disruption. The acidic
pH of the stratum corneum inhibits serine protease activity,
but with the increase in pH after permeability barrier
disruption, the activity of the serine proteases in the stratum
corneum increases, leading to an enhanced activation of
PAR2. 46,48,49 Topically applied PAR2 agonists inhibit
lamellar body secretion and permeability barrier repair. 47
Conversely, PAR2-deficient mice have accelerated perme-
ability barrier repair. 46 Thus, similar to nitric oxide,
signaling via PAR2 is an inhibitory signal that delays
permeability barrier repair.
Although the extracellular lipid enriched lamellar mem-
branes in the stratum corneum are primarily responsible for
the barrier that stops water and electrolyte movement,
corneocytes are also required. Acute disruption of the
permeability barrier leads to the accelerated conversion of
stratum granulosum cells to corneocytes. 50 This acceleration
of corneocyte formation is blocked by serine protease
inhibitors or acidification of the stratum corneum, which
reduces serine protease activity. 50 Corneocyte formation is
delayed in PAR2-deficient mice 50; thus, PAR2 signaling
delays lamellar body secretion but accelerates the formation
of corneocytes.
Effect of hormones on permeability
barrier function
Prolonged exposure to glucocorticoids leads to a defect
in basal permeability barrier function. 51,52 Although short-
term (several days) topical or systemic treatment with
glucocorticoids does not adversely affect basal permeability
barrier function, it does delay the recovery of permeability
barrier function after acute disruption. 53 Glucocorticoids
decrease the production and secretion of lamellar bodies,
which results in decreased extracellular lamellar membranes
in the stratum corneum. 53 This decrease in lamellar body
formation is accounted for by a glucocorticoid-induced
decrease in epidermal lipid synthesis, and the abnormality
K.R. Feingold, M. Denda
in permeability barrier homeostasis induced by glucocorti-
coid treatment can be corrected by topical lipid administra-
tion. 53 Of note, psychologic stress increases glucocorticoid
production and thereby results in defects in permeability
barrier function. 54,55
Similar to glucocorticoids, testosterone also adversely
effects permeability barrier function. 56 Lipid synthesis is not
altered by testosterone status, but lamellar body formation
and secretion are both decreased, resulting in a reduction in
extracellular lamellar membranes in the stratum corneum. 56
The mechanism by which testosterone decreases lamellar
body formation is unknown.
The effect of thyroid hormone, insulin, and other
hormones on permeability barrier function in adult animals
has not been extensively studied. Limited studies suggest
that estrogen does not have major effects on permeability
barrier homeostasis. 57
Conclusions
The formation of a competent permeability barrier is an
absolute requirement for terrestrial life, and therefore, it is
not surprising that a large number of factors regulate its
formation. Some factors accelerate permeability barrier
formation (decreases in calcium in the outer epidermis,
cytokines, PPARs, LXR, and growth factors) and others
inhibit permeability barrier formation (nitric oxide, PAR2
activation, glucocorticoids, and testosterone). The ability of a
variety of factors to regulate permeability barrier formation
allows for a more precise and nuanced regulation.
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