ARTICLE
Auteur(s) : Saveria
Pastore1, Francesca Mascia1, Giampiero
Girolomoni2
1Laboratory of Tissue Engineering and Cutaneous
Physiopathology, Istituto Dermopatico dell’Immacolata, IRCCS, via
Monti di Creta 104, 00167 Roma, Italy
2Department of Dermatology, University of Verona,
Piazzale A. Stefani 1, 37126 Verona, Italy
accepté le 15 Novembre 2005
Atopic diseases are genetically determined disorders affecting
exclusively tissues such as the skin, the conjunctiva and the
respiratory mucosa, which demarcate the host from the environment.
In contrast, the gastrointestinal tract and genital mucosae, which
also provide a large interface with the outside, do not undergo
atopic disorders, not at least according to their current
definition. The reasons why only selected tissues develop atopic
diseases are probably very complex, but at least two hypotheses can
be put forward. First, the immune system may be altered to react
with exaggerated responses to apparently harmless antigens
(allergens) that reach the skin and respiratory surfaces. Secondly,
these tissues may harbor resident (and thus tissue specific) cells
with an abnormal capacity to control inflammatory responses [1].
Atopic diseases are indeed characterized by IgE hyperresponsiveness
to environmental allergens and a peculiar hyperreactivity of the
target tissues toward a variety of inflammatory stimuli. The latter
aspect is always present, whereas the former is not constant. In
fact, up to 40% of patients with atopic dermatitis (AD) or
bronchial asthma do not show elevated serum IgE or specific IgE
[2]. Recent acquisitions have also demonstrated that any
perturbation of the epidermal permeability barrier represents per
se an effective mechanism leading to cutaneous inflammation, since
numerous cytokines, chemokines and some of the growth factors
released by keratinocytes as autocrine regulators of barrier
homeostasis can also favor the development of inflammatory
reactions [3]. Furthermore, a defective permeability barrier leads
to the penetration of environmental allergens into the epidermis
and hence facilitates the initiation of the allergen-specific
immunological reactions known to be involved in the pathogenesis of
AD [4].
Initiation and amplification of inflammatory skin
disorders
Infiltrating leukocytes release cytokines which maximally stimulate
keratinocytes to express soluble and membrane mediators with a
primary role in the recruitment, retention and activation of T
cells and other leukocytes in the skin. Interferon (IFN)-γ is the
best-characterized proinflammatory cytokine for keratinocytes.
IFN-γ-producing T cell clones dominate psoriasis and allergic
contact dermatitis lesions, but also intervene in the establishment
of chronic AD lesions [5-7]. After exposure to IFN-γ, keratinocytes
express on their surface the intercellular adhesion molecule
(ICAM)-1 for T cell retention in the epidermis. Basal and
suprabasal keratinocytes of chronic AD lesions express ICAM-1,
although not to the extent observed in allergic contact dermatitis
or psoriasis, and this expression can be an indicator of the
presence of some IFN-γ-releasing T cells in the underlying
infiltrate. Moreover, IFN-γ up-regulates MHC class I molecules,
induces de novo synthesis of mature MHC class II molecules and
upregulates Fas expression, thus rendering keratinocytes sensitive
to T cell-mediated Fas-dependent apoptosis. During the early phases
of keratinocyte apoptosis, E-cadherin is cleaved by caspases. The
loss of E-chaderin weakens intercellular contacts between
keratinocytes and contributes to the formation of epidermal
spongiosis, which characterizes eczema [8]. IFN-γ induces
keratinocyte expression of cytokines with a well-recognized role in
skin inflammation, including interleukin (IL)-1α, IL-1 receptor
antagonist (IL-1ra), tumor necrosis factor (TNF)-α and GM-CSF, and
a variety of chemokines active in T cell attraction, including
CXCR3 ligands and MCP-1/CCL2 [5-7]. In the context of AD
inflammation, histamine, which is an essential effector molecule of
IgE-mediated allergic responses, may also strengthen the
pro-inflammatory behaviour of keratinocytes. These cells
constitutively express a functional H1 type receptor on their
surface, and stimulation of this receptor concomitant with IFN-γ
leads to a stronger expression of numerous mediators including
GM-CSF, MCP-1, RANTES/CCL5, MIP-3α/CCL20 and IP-10/CXCL10 [9].
Among T cell-derived cytokines abundantly released in the skin
in the course of AD, IL-4 has been characterized as an active
contributor to keratinocyte activation only recently [10]. Cells
expressing IL-4 can be detected even in the uninvolved skin of
patients with AD, and their number increases prominently in acute
and chronic lesions. Keratinocytes express functional IL-4
receptors, and although IL-4 alone has a modest capacity to induce
cytokine release by keratinocytes, it effectively reinforces the
activity of IFN-γ and TNF-α in the induction of CXCR3 agonistic
chemokines, and hence reinforces Th1 lymphocyte attraction into the
inflamed skin [10]. Furthermore, IL-4 was recently shown to
actively oppose ceramide up-regulation by TNF-α and IFN-γ in
keratinocytes of organ skin cultures or in vitro reconstructed skin
equivalents, and in parallel to increase trans-epidermal water loss
(TEWL) in both these models [11]. This mechanism could reasonably
contribute to aggravate the disruption of the permeability barrier
function in AD lesions.
Recruitment of inflammatory cells in AD
The inflammatory infiltrate of AD consists predominantly of
dendritic cells (DCs) and memory CD4+ T cells [12, 13].
Essentially all T cells infiltrating the skin lesions express the
cutaneous lymphocyte-associated antigen (CLA), which functions as a
skin homing receptor by mediating T lymphocyte rolling over
E-selectin expressed by activated endothelial cells. Chemokine
receptors are important players in the tissue targeting of T
lymphocytes. In line with this concept, it has been shown that
skin-seeking CLA+ T cells co-express the CCR4 receptor,
which is the ligand of TARC/CCL17 and MDC/CCL22. Th2 compared to
Th1 lymphocytes preferentially express CCR4. The proportion of
CD4+ T lymphocytes expressing the CCR4 receptor in the
peripheral blood of patients with AD is higher compared to healthy
controls. In addition, CCR4+CD4+ T cells
abundantly infiltrate AD lesions, indicating not only increased
generation of CCR4+ T cells, but also enhanced
recruitment into AD skin.
Keratinocytes express numerous chemotactic signals for T
lymphocytes, including RANTES, MCP-1, CTACK/CCL27, PARC/CCL18,
MIP-3α/CCL20, IL-16 and TARC/CCL17 [6, 7, 14, 15]. Both RANTES and
MCP-1, which are active on both Th1 and Th2 cells, are strongly
expressed by keratinocytes in the diseased skin [16], while
elevated RANTES can also be found in the serum of AD patients [17].
Interestingly, in vitro studies showed that keratinocytes from AD
patients produced increased amounts of RANTES, but reduced levels
of IP-10, when compared to keratinocytes from normal controls or
patients with psoriasis [16]. Acute and chronic AD lesions also
exhibit strong CTACK expression, which correlates with the
increased number of CCR10+ T cells infiltrating these
lesions [18, 19]. Compared to psoriasis, AD lesions present higher
levels of PARC transcript [19]. This chemokine, whose receptor is
not known, mediates skin homing of memory T cells in AD. Notably,
PARC has been recently described as the most highly expressed
chemokine in AD, with DCs representing its major producers [20]. A
boost in its expression in the skin of AD patients follows the
exposure to the relevant allergen or the staphylococcal
superantigen enterotoxin B [21]. These observations suggest an
important role for PARC in the initiation and amplification of AD
skin inflammation. Also the specific transcript of MIP-3α can be
found expressed in AD skin although less abundantly than in
psoriasis [19]. Immunostaining localized this chemokine in the
basal epidermis and identified its responding (CCR6+)
cells mainly as DCs and T cells [22]. Interestingly, disruption of
the epidermal permeability barrier upregulates MIP-3α mRNA in the
epidermis, revealing an important mechanism for the initial influx
of DCs and T cells in AD skin [22]. In acute and, to a lesser
extent, chronic AD lesions, enhanced keratinocyte expression of
IL-16 mRNA has been associated with increased numbers of
skin-infiltrating CD4+ cells, while Langerhans cells
have been recognized as the most relevant source of this chemokine
in this disease [23]. Indeed, IL-16 is strongly chemotactic for
different CD4+ cells, which include CD4+ T
cells and CD4-bearing eosinophils as well as DCs, and FcεRI
engagement was shown to upregulate IL-16 production in Langerhans
cells derived from atopic donors [24]. The ligands for CCR4 are
TARC and MDC, mostly produced by DCs [25, 26]. A strong correlation
with disease activity was recently found for TARC serum levels
[27]. TARC is found expressed on microvascular endothelial cells in
AD lesions, and therefore these cells may be centrally involved in
the arrest of circulating CCR4+ T cells [26]. Together
with mast cells and endothelial cells, DCs are also abundant
sources of I-309/CCL1 in AD skin [28]. Contact with significant
allergens was shown to induce the expression of this chemokine,
which acts through CCR8, in turn expressed on small subsets of
circulating T cells, monocytes and DCs. In vitro, IgE binding and
cross-linking on the surface of mast cells was shown to effectively
up-regulate the release of this chemokine [28]. Another mediator
strongly expressed by the microvascular endothelium is
fraktalkine/CX3CL1, which thus appears involved in the recruitment
of the CX3CR1-positive leukocytes in AD lesions [29]. Finally, in
the context of acute and chronic AD lesions, resident cell
populations contribute to the attraction of eosinophils mainly
through the release of CCR3 binding molecules, including RANTES,
MCP-4/CCL13 and eotaxin/CCL11 [19]. ( Figure 1 ) presents a
schematic overview of the central role of keratinocyte activation
in the cellular and molecular mechanisms underlying AD.
There is currently an increasing interest in defining the role
of the over-expression of epidermal growth factor receptor (EGFR)
and its ligands (TGF-α and HB-EGF) in the epithelia affected by
chronic inflammatory disorders. The EGFR-ligand system plays a
fundamental role in self-protection and response to injury [30]. By
contrast, EGFR activation was correlated with sustained IL-8/CXCL8
expression and strong neutrophilia in the broncho-alveolar lavage
fluid of asthma patients [31, 32]. EGFR activation is a valid
stimulus to induce IL-8 expression in all epithelial cells,
including keratinocytes [31-34]. Recently, however, a deeper
investigation into the effects of EGFR activation unveiled its
complex role in the control of chemokine expression in skin
keratinocytes both in vitro and in vivo. In particular, we could
observe that EGFR-driven signaling down-regulates the expression of
a cluster of chemokines implicated in the leukocyte recruitment
into the epidermis, including MCP-1, RANTES and IP-10 [33, 34].
Activation of extracellular-signal regulated kinase 1,2 (ERK1/2)
mediates these regulatory events, which take place at the
post-transcriptional level, via the control of chemochine
transcript half-life [35]. These observations indicate that
targeting EGFR should not invariably be considered an attractive
therapy in the inflammatory skin disorders associated with
epithelial hyperproliferation, and that further analyses are
necessary to better define its specific involvement in atopic
diseases.
Keratinocytes from AD patients produce increased amounts of
GM-CSF and other pro-inflammatory cytokines
GM-CSF is readily produced by epithelial cells in response to
autocrine IL-1α and TNF-α, and to T cell-derived cytokines such as
IFN-γ, IL-4, and IL-17 [10]. It promotes the proliferation and
survival of keratinocytes, T cells, eosinophils, monocytes and DC
precursors. In addition, GM-CSF favors the recruitment and
activation of monocytes, basophils, eosinophils and DCs. Finally,
GM-CSF together with IL-4 induces differentiation of DCs from
monocyte precursors, a phenomenon that may be particularly relevant
to the pathophysiology of AD. Of note, lesional skin of AD patients
exhibits an increased number of cells belonging to the DC lineage,
including epidermal Langerhans cells, dermal DCs, and a unique
population of CD1a+ DCs expressing CD1b and/or CD36,
which closely resemble DCs generated in vitro by culturing
monocytes in the presence of GM-CSF and IL-4. Such DCs can
efficiently present IgE-bound allergens to T lymphocytes, since
they display an upregulated expression of the high affinity (FcεRI)
IgE receptor [36]. In the context of atopic diseases, increased
expression of GM-CSF has been documented in nasal and bronchial
epithelial cells of rhinitis and asthma patients, respectively, as
well as in peripheral blood mononuclear cells of AD patients [13].
Furthermore, we have shown that GM-CSF is overexpressed in
keratinocytes of AD lesions, and that keratinocytes cultured from
nonlesional skin of adult AD patients produce higher levels of
GM-CSF both basally and in response to IL-1α, IFN-γ or phorbol
esters, when compared to keratinocytes from nonatopic individuals
[37, 38]. In addition, supernatants from atopic keratinocytes are
able to strongly stimulate mononuclear cell proliferation in a
GM-CSF-dependent manner, and conditioned medium from phorbol
myristate acetate (PMA)-treated AD keratinocytes together with
exogenous IL-4, can support phenotypical and functional
differentiation of peripheral blood monocytes into DCs [37]. These
findings could explain the persistence of a heavy infiltrate of
“inflammatory” DCs in AD skin. The relevant role of GM-CSF
overexpression is emphasized by a rat compartmentalized transgene
model, where a prolonged skin expression of GM-CSF induced changes
commonly observed in AD [39]. Recent studies have shown that AD
keratinocytes express high levels of thymic stromal lymphopoietin
(TSLP), a factor that activates myeloid DCs to increased expression
of chemokines active towards CCR4+ Th2 lymphocytes [40,
41]. Skin-restricted overexpression of TSLP in a transgenic mouse
results in an AD-like phenotype, with the development of eczematous
lesions, a dramatic increase in Th2 T cells expressing cutaneous
homing receptors and elevated serum levels of IgE [42]. Moreover,
as we previously mentioned, resting and activated AD keratinocytes
release higher amounts of RANTES compared to keratinocytes from
psoriatic patients and healthy controls [16].
The distinct propensity of keratinocytes to produce higher than
normal levels of growth factors (GM-CSF), chemokines (RANTES), and
cytokines (TSLP) may greatly stimulate DC differentiation from
precursors, and recruit as well as activate DCs in AD skin (( figure 2 )). The
biochemical mechanisms underlying excessive production of certain
proinflammatory mediators by epithelial cells are probably
multiple. Numerous functional polymorphisms in the
regulatory/coding regions of clusters of cytokine/chemokine genes,
including RANTES, have been found in AD patients, which could be
implicated in an overproduction by keratinocytes. However, apart
from genes coding for Th2 cytokines, polymorphisms for other
inflammatory genes were not confirmed in other studies [43, 44].
More interestingly, an altered response to inflammatory stimuli
could confer specific tissue targeting of the atopic syndrome. In
searching for a molecular mechanism underlying abnormal cytokine
production in AD keratinocytes, we have examined GM-SCF expression
following PMA stimulation [38]. GM-CSF gene transcriptional
activity was significantly stronger in AD keratinocytes, both in
unstimulated and in PMA-stimulated conditions, and it could be
correlated with higher nuclear levels and DNA binding activity of
activator protein-1 (AP-1) complexes. More recently, abnormal AP-1
activation was also confirmed in peripheral blood mononuclear cells
isolated from AD patients following in vitro stimulation with IL-4
[45]. AP-1 is critically implicated in fundamental processes of
cell physiology, including keratinocyte proliferation and
differentiation [46]
The mechanism underlying enhanced AP-1 activation in cells from
AD donors is presently uncharacterized. However, it is possible
that abnormal ceramide expression in AD keratinocytes plays some
role in this process. Intracellularly, ceramides can compete with
the activating binding of diacyl glycerols on distinct protein
kinase C (PKC) isozymes, and interfere with PKC functions [47]. A
defect in ceramide generation could therefore result in enhanced
PKC activation, leading to a dysregulated AP-1 activation and
eventually to hyperproduction of GM-CSF and other pro-inflammatory
cytokines by AD keratinocytes. An important role of AP-1 has been
indicated also in bronchial asthma. Recently, a selective inhibitor
of AP-1 function proved therapeutically effective in a mouse asthma
model [48].
Mechanisms involved in the alteration of epidermal barrier
function
Much of the barrier function of human epidermis against the
environment is provided by the cornified cell envelope (CE), an
assembly of several structural proteins and lipids that forms the
endpoint of keratinocyte differentiation and death [49]. The CE
replaces the plasma membrane of differentiating keratinocytes and
consists of keratins that are enclosed within an insoluble matrix
of proteins, which in turn are crosslinked by transglutaminases and
surrounded by a ceramide-rich lipid envelope. Indeed, both protein
and lipid components are essential for an optimal barrier function,
as demonstrated by genetic defects underlying several human
diseases and mouse models [49, 50]. In particular, recent findings
have provided evidence that a disturbed protease-antiprotease
balance could cause faulty differentiation processes in the
epidermis [50, 51].
The existence of a defective permeability barrier function in
the skin of AD patients is well accepted, and the epidermal
abnormality, generally viewed in the past as a consequence of the
inflammatory phenotype, is now considered the outcome of a
pre-existing defect of epidermal differentiation [4]. TEWL is found
increased both in dry non-eczematous skin and in apparently normal
skin of patients with AD, although a further barrier permeability
loss correlates with the degree of inflammation in lesional skin.
In the lesion, a contribution to this defect could come from
IL-4-induced down-regulation of ceramide expression by
keratinocytes, as previously commented [11]. However, a complex
defect of total lipids, sterol esters and phospholipids including
sphingomyelin, as well as an increase in free fatty acids and
sterols compared to normal controls, characterizes the skin of AD
patients even in the absence of inflammation [4]. Furthermore,
evidence exists that both non-lesional and lesional skin of AD
patients contains elevated levels of a sphingomyelin deacylase,
with a consequent reduction of ceramide synthesis due to the
preferential hydrolysis of sphingomyelin into free fatty acids and
phosphorylcoline [52]. More recently, the activities of the enzymes
crucially involved in ceramide generation in the skin, namely
acidic and neutral sphingomyelinase (A- and N-SMase), were found
prominently reduced in both non-lesional and lesional AD skin when
compared to healthy controls, and reduced A-SMase activity was
correlated with decreased ceramide content [53]. Being ceramide
content in the stratum corneum closely correlated with its barrier
function, these enzymatic defects may represent major
predisposition factors to AD inflammation.
Dysregulated serine proteinase activity
Cornification requires a massive activation of epidermal proteases,
although for most of these their precise role remains elusive
[49-51]. Cysteine- and serine-protease inhibitors are abundantly
expressed in the epidermis, suggesting an important role in the
control of protease activity. Extracellular proteases are
particularly abundant in the CE and are involved in the control of
desquamation. Corneodesmosomal proteins that are degraded during
desquamation include desmoglein-1, desmocollin-1, plakoglobin and
corneodesmosin. The enzymes that are responsible for their
degradation are not yet fully identified, although the major
candidates include stratum corneum chymotryptic enzyme (SCCE),
stratum corneum tryptic enzyme (SCTE) and stratum corneum
cathepsin-L-like enzyme (SCCL). The presence of these enzymes is
strictly confined to the differentiating suprabasal layers of the
epidermis.
The clinically asymptomatic skin of AD patients typically shows
a thinner CE as well as a reduced mean corneocyte area. In
addition, AD patients release more corneocyte clumps from the skin
surface in forced desquamation studies, strongly suggesting that
abnormal desquamation is an underlying feature in AD [4].
Independent groups have recently suggested the involvement of a
dysregulated serine protease activity in the development of AD.
Hansson and coworkers found that a transgenic mouse model
over-expressing human SCCE exhibited severe symptoms of chronic
itchy dermatitis resembling AD [54]. In addition, an association
was recently found between a genetic variant (AACC insertion) in
the coding region of SCCE and AD [55], which is now under further
investigation for a possible pathophysiological meaning. Being SCCE
active also in the proteolytic degradation of distinct lipid
processing enzymes including A-SMase [56], enhanced SCCE function
could reasonably provide a direct link between enhanced serine
protease activity and reduced ceramide expression in atopic skin.
The importance of regulated proteolysis in epithelia is well
demonstrated by the discovery of the Kazal-type 5 serine protease
inhibitor, Spink5 as the defective gene in Netherton syndrome [57].
The defective inhibitory regulation of the protein product of
Spink5 LEKT1 results in increased protease activity in the stratum
corneum, accelerated degradation of desmoglein-1 and
over-desquamation of corneocytes [58]. LEKTI is strongly expressed
in differentiated keratinocytes in normal skin, and the lamellar
granule system has been shown to transport and secrete LEKTI
earlier than SCCE and SCTE, reasonably in order to prevent unproper
loss of CE integrity [59]. Previously, Walley and coworkers
identified six polymorphisms in Spink5 and found that a Glu420Lys
variant in LEKTI shows significant association with atopy including
AD in two independent panels of families [60].
With regard to LEKTI-targeted enzymes, serine proteinases can
mediate pro-inflammatory effects via the proteinase-activated
receptor-2 (PAR-2), one of the four members of a new subfamily of
G-protein receptors known to be highly expressed on epidermal
keratinocytes and dermal endothelial cells. These cell populations
respond to PAR-2 signalling with hyper-proliferation and enhanced
expression of pro-inflammatory cytokines and chemokines [61]. PAR-2
over-activation could also be importantly involved in the
development of pruritus [62]. Endogenous PAR-2 activators may
include mast cell-derived tryptase and other trypsin-like enzymes
such as SCTE, whereas exogenous activators could be tryptic enzymes
released by Staphylococcus aureus and house dust mites. Indeed,
several constituents of house dust mites can sustain a non-immune
specific inflammatory reaction via their serine proteinase activity
in parallel with the elicitation of an allergen-specific
response.
Chymase is a chymotrypsin- and cathepsin G-like serine
proteinase released by mast cells. Due to their strong expression
of the high-affinity IgE receptor, mast cells are well-recognized
crucial effectors of IgE-dependent reactions. Upon IgE receptor
aggregation via IgE binding, mast cells release a plethora of
preformed and newly synthesized mediators, including large
quantities of chymase. Apart from its possible direct involvement
in fibrosis and tissue remodeling, chymase exhibits chemotactic
activity for human polymorphonuclear leukocytes in vitro and on
eosinophils in vivo [63]. Recent data have confirmed previous
observations of a significant association between polymorphism in
the coding region of chymase promoter and AD but no association
with serum IgE levels, and support the hypothesis that it may serve
as a candidate gene for this disease [64].
Conclusion
Keratinocytes participate to the pathogenesis of AD through the
production of numerous inflammatory signals, which initiate,
amplify and sustain skin inflammation. It is likely that genetic
abnormalities in the homeostatic mechanisms controlling
keratinocyte differentiation affect the constitutive and induced
production of mediators by AD keratinocytes along complex patterns
involving inflammatory genes themselves and/or signal transduction
pathways. Together, these alterations direct the specific
expression of the atopic state to the skin. A further advancement
in the understanding of the complex molecular bases of abnormal
keratinocyte behavior in AD may ultimately lead to the
identification of novel targets for specific and effective
therapeutic intervention.
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