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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


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

disruption, there are marked alterations in the underlying The lipids secreted by stratum granulosum cells must be
viable epidermis that result in the rapid restoration of processed in the extracellular space of the stratum corneum
permeability barrier function toward normal. 2 By 6 hours for the formation of mature functional lamellar membranes
after acute barrier disruption, greater than 50% of perme- that impede water and electrolyte movement. 2 Lamellar
ability barrier function is restored in mice. 2,5,6 The rate of bodies secrete lipid into the extracellular spaces of the
recovery is faster when the degree of barrier disruption is stratum corneum and also specific enzymes involved in the
greater. 5 Permeability barrier function in humans is also extracellular processing of lipids. Specifically, glucosylcer-
rapidly restored toward normal after acute barrier disruption, amides must be metabolized to ceramides, a reaction
but the rate of recovery is slower than in mice. 7 The catalyzed by β-glucocerebrosidase; sphingomyelins must
metabolic response in humans to permeability barrier be converted to ceramides, a reaction catalyzed by acid
disruption is also very similar to what is observed in mice. 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
Metabolic changes in the epidermis that
expression of β-glucocerebrosidase and acid sphingomye-
restore permeability barrier function linase, which would facilitate the formation of mature
functional lamellar membranes. 2
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 Role of calcium in the homeostatic
granulosum cells secrete a large percentage of their stored repair response
lamellar bodies, so that only a small number of lamellar
bodies remain in the cytoplasm of these cells. 2 The In the epidermis, there is calcium gradient, with high
stratum granulosum cells begin to rapidly synthesize new concentrations of calcium observed in the upper epidermis
lamellar bodies and continue to secrete these newly formed (stratum granulosum) and low concentrations of calcium
lamellar bodies. observed in the lower epidermis (basal layer). 9 Immedi-
Simultaneous with the formation of these new lamellar ately after acute barrier disruption, the increased water
bodies is an increase in messenger RNA levels and activity of movement through the defective stratum corneum carries
key enzymes such as 3-hydoxy-3-methyl-glutary-coenzyme calcium outward, resulting in loss of the calcium gradient,
A (HMG-CoA) reductase, squalene synthase, acetyl-coen- with a marked decrease in the calcium localized to the
zyme A carboxylase, fatty acid synthase, and serine upper epidermis. 10,11 Maintaining a high calcium concen-
palmitoyl transferase, resulting in an increase in cholesterol, tration in the upper epidermis after barrier disruption by
fatty acid, and ceramide synthesis above their already high immersing the skin in a high calcium solution blocks
basal levels in the epidermis. 2 In addition to an increase in lamellar body secretion and inhibits normal permeability
the mass of HMG-CoA reductase, the catalytic activity of barrier repair. 10-12 If the calcium content in the upper
this enzyme also increases due to a change in phosphory- epidermis is lowered by iontophoresis or sonophoresis,
lation state. Inhibition of cholesterol, fatty acid, or ceramide without disrupting the permeability barrier, lamellar body
synthesis blocks the formation of new lamellar bodies and secretion is stimulated. 13,14 These results indicate that
permeability barrier recovery is delayed, indicating that this calcium levels in the upper epidermis are a key signal that
increase in de novo synthesis of lipids is required for new regulates lamellar body secretion. Parallel changes in other
lamellar body formation. 2 ions, such as potassium, are also important regulators of
In addition to de novo lipid synthesis, extraepidermal lamellar body secretion and permeability barrier repair. 10,15
lipids also are a source of lipids for lamellar body formation. The calcium inhibition of permeability barrier repair can
After permeability barrier disruption, there is an increase in be blocked by verapamil and nifedipine, which block
the receptors that mediate the uptake of lipoproteins (low- calcium transport into cells by the L-channel. 10 Calmodulin
density lipoprotein receptor and scavenger receptor class B inhibitors, trifluoroperazine, or N-6-aminohexyl-5-chloro-1-
member 1) and the transporters that facilitate the entry of naphthalenesulfonamide, also reduced the ability of exoge-
fatty acids into cells, including fatty acid transport protein 1 nous calcium to inhibit permeability barrier recovery. 10 The
(FATP-1), FATP-6, and cluster of differentiation (CD) 36. 2 precise pathways and mechanisms by which increased levels
In addition, adenosine triphosphate (ATP)-binding cassette of intracellular calcium inhibit lamellar body secretion by
transporter 1 (ABCA1), a transporter that effluxes choles- keratinocytes remain to be elucidated, however.
terol and phospholipids from cells to high-density lipopro- Although these studies show that decreases in calcium
tein, is decreased after permeability barrier disruption, which in the outer epidermis signal lamellar body secretion and
would increase the amount of lipid available for lamellar permeability barrier repair, the increased concentrations
body synthesis. 8 of calcium in the outer epidermis depend on normal
Regulation of permeability barrier homeostasis 265

permeability barrier function. The restoration of the corneocyte envelope proteins, and increase the expression of
calcium gradient after acute permeability barrier disruption transglutaminase 1, a crucial enzyme for the cross-linking of
closely parallels the normalization of permeability barrier cornified envelope proteins. 27 Activation of PPARs and
function. 16,17 Delaying or accelerating the restoration of LXRs also stimulates permeability barrier recovery after
the permeability barrier function also accelerates or delays acute barrier disruption. 27,28 Studies have further shown that
the formation of the calcium gradient. 16,17 In a similar PPAR and LXR activation stimulates epidermal lipid
fashion, the appearance of the calcium gradient during synthesis, increases ABCA12 expression, accelerates lamel-
fetal development occurs simultaneously with the forma- lar body secretion, and increases the activity of the enzymes
tion of the permeability barrier. 18 Accelerating or delaying required for the extracellular processing of lipid, which
permeable barrier formation in the fetus also affects the together likely accounts for the improvement in permeability
development of the calcium gradient. 18 Together these barrier homeostasis. 27-29 Of note in PPAR- β/δ–deficient
observations indicate that the formation of the calcium mice, recovery of permeability barrier recovery is delayed,
gradient in the epidermis depends on normal permeability indicating that this receptor plays a physiologic role in
barrier function. Because a large portion of the calcium in mediating permeability barrier homeostasis. 30
the epidermis is localized intracellularly in organelles Vitamin D and the vitamin D receptor also regulate
such as the endoplasmic reticulum and Golgi, it is likely permeability barrier formation. Mice deficient in 25 hydro-
that other factors also influence calcium localization in xyvitamin D1 α-hydoxylase, which is required for the
the epidermis. 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
Role of other signaling pathways in stimulating
also have defects in permeability barrier homeostasis due to a
the homeostatic repair response decrease in the number of lamellar bodies. 32 Thus, the
activation of a number of different nuclear hormone
Keratinocytes produce a wide array of cytokines, receptors (PPARs, LXR, and vitamin D receptor) is involved
including tumor necrosis factor and interleukin 1α (IL-1α), in regulating lamellar body formation and secretion and
IL-1β, and IL-6. Disruption of the permeability barrier also permeability barrier homeostasis.
increases the expression of these cytokines. 19,20. Studies in Keratinocytes express many of the same receptors that
mice deficient in these cytokines or their receptors have are expressed in neurons, including histamine (H1 and H2),
shown delays in permeability barrier recovery after acute γ-aminobutyric (type A), β-2-adrenergic, glycine, glutamate
disruption, suggesting that the increased cytokine production (N-methyl D-aspartate type), dopamine (D2), transient
facilitates barrier repair. 21,22 Cytokines are well known to receptor potential channels (TRP) V1, TRPV4, TRPA1,
stimulate lipid synthesis and metabolism, and one could and TRPM8, and nicotinic acetylcholine receptors. Studies
anticipate that an increase in epidermal lipids induced by have shown that stimulating or inhibiting these receptors
cytokines could facilitate lamellar body formation and with exogenous ligands can accelerate or inhibit perme-
permeability barrier recovery. 21,23,24 ability barrier repair. 33-42 At this time, it is unknown
In addition to cytokines, growth factors are also likely whether the production of the ligands for these receptors is
involved in regulating permeability barrier repair. After altered by permeability barrier disruption and whether these
acute disruption of the permeability barrier, there is an pathways play a physiologic role in regulating permeability
increase in the expression of growth factors, such as barrier repair.
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 Role of signaling pathways in inhibiting the
barrier repair is delayed in VEGF-deficient mice, indicating homeostatic repair response
that this growth factor is important in facilitating perme-
ability barrier repair. 25 Studies have demonstrated an important role of nitric
Peroxisome proliferator-activated receptor-α (PPAR-α), oxide in inhibiting permeability barrier repair. 43-45 They
PPAR-β/δ, PPAR-γ, and liver X receptor-α (LXR-α) and demonstrated that:
LXR-β, are expressed in cultured human keratinocytes and
murine epidermis. 27 Activation of PPARs by fatty acids and • Permeability barrier disruption enhanced nitric oxide
exogenous ligands such as clofibrate and LXRs by production and could be blocked by a neuronal nitric
oxysterols and exogenous ligands, such as TO901317, oxide synthase (nNOS) inhibitor, but not by an
regulate the expression of many important aspects of inducible nitric oxide synthase (iNOS) inhibitor.
keratinocyte metabolism. 27 Activation of PPARs and • Topical application of an nNOS but not an iNOS
LXRs stimulate involucrin and loricrin expression, key inhibitor accelerated permeability barrier recovery.
266 K.R. Feingold, M. Denda

• Permeability barrier recovery was also accelerated in in permeability barrier homeostasis induced by glucocorti-
nNOS-deficient mice but not in iNOS-deficient mice. coid treatment can be corrected by topical lipid administra-
• Endothelial nitric oxide synthase (eNOS)-deficient tion. 53 Of note, psychologic stress increases glucocorticoid
mice also have a faster recovery of permeability barrier production and thereby results in defects in permeability
function after acute disruption. barrier function. 54,55
Similar to glucocorticoids, testosterone also adversely
Together these results demonstrate that increased nitric effects permeability barrier function. 56 Lipid synthesis is not
oxide production delays permeability barrier repair. altered by testosterone status, but lamellar body formation
Studies have also demonstrated that proteinase-activated and secretion are both decreased, resulting in a reduction in
receptor 2 (PAR2) is involved in delaying permeability extracellular lamellar membranes in the stratum corneum. 56
barrier repair. 46 PAR2 is activated by trypticlike serine The mechanism by which testosterone decreases lamellar
proteases, and after permeability barrier disruption, there is body formation is unknown.
an increase in serine protease activity. 46,47 The basis for this The effect of thyroid hormone, insulin, and other
increase in serine protease activity is related to changes in hormones on permeability barrier function in adult animals
stratum corneum pH. 48,49 Under usual circumstances, the has not been extensively studied. Limited studies suggest
pH of the stratum corneum is acidic (pH 5.0-5.5), but the pH that estrogen does not have major effects on permeability
increases after permeability barrier disruption. The acidic barrier homeostasis. 57
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
Conclusions
PAR2. 46,48,49 Topically applied PAR2 agonists inhibit
lamellar body secretion and permeability barrier repair. 47 The formation of a competent permeability barrier is an
Conversely, PAR2-deficient mice have accelerated perme- absolute requirement for terrestrial life, and therefore, it is
ability barrier repair. 46 Thus, similar to nitric oxide, not surprising that a large number of factors regulate its
signaling via PAR2 is an inhibitory signal that delays formation. Some factors accelerate permeability barrier
permeability barrier repair. formation (decreases in calcium in the outer epidermis,
Although the extracellular lipid enriched lamellar mem- cytokines, PPARs, LXR, and growth factors) and others
branes in the stratum corneum are primarily responsible for inhibit permeability barrier formation (nitric oxide, PAR2
the barrier that stops water and electrolyte movement, activation, glucocorticoids, and testosterone). The ability of a
corneocytes are also required. Acute disruption of the variety of factors to regulate permeability barrier formation
permeability barrier leads to the accelerated conversion of allows for a more precise and nuanced regulation.
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
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