Clinics in Dermatology (2007) 25, 581588

Resident skin cells in psoriasis: a special look at the pathogenetic functions of keratinocytes
Cristina Albanesi, PhD a,, Ornella De Pit, MD a , Giampiero Girolomoni, MD b
Laboratory of Immunology and Allergology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome, Italy Department of Biomedical and Surgical Sciences, Section of Dermatology and Venereology, University of Verona, Verona, Italy
b a

Abstract Psoriasis is a chronic inflammatory skin disease characterized by exaggerated keratinocyte proliferation. Current paradigm indicates that psoriasis is driven by T cellmediated immune responses targeting keratinocytes. However, psoriasis cannot be explained solely on the basis of T-cell activation, and it is likely that intrinsic alterations in epidermal keratinocytes play a very relevant role in disease expression. In particular, keratinocytes may be important in initiating, sustaining, and amplifying the inflammatory responses by expressing molecules involved in T-cell recruitment, retention, and activation. Keratinocytes are also a relevant source of growth factors for angiogenesis. Finally, intrinsic defects in cytokine and growth factor signaling in keratinocytes may be responsible for their aberrant hyperproliferation and differentiation to T cellderived signals. Other skin resident cells such as fibroblasts, mast cells, and endothelial cells also contribute to psoriasis pathogenesis by expressing molecules involved in T-cell recruitment and activation. 2007 Elsevier Inc. All rights reserved.

Introduction
Despite an intense effort in the search for the primary cause of psoriasis, it is still controversial as to whether this common skin disease results from an intrinsic abnormality in epidermal keratinocytes and/or from deregulation of the immune system. The hypothesis that psoriasis is primarily a keratinocyte proliferation disorder is suggested by the pathologic development of a hypertrophic cutaneous barrier. However, it is well defined that T cells (adaptive immunity) have a role in keratinocyte turnover and growth in psoriasis. Nevertheless, the recently acquired insight that antitumor necrosis factor (TNF-) therapies are highly effective suggests the presence of pathologic activation of innate
Corresponding author. E-mail address: c.albanesi@idi.it (C. Albanesi). 0738-081X/$ see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2007.08.013

immunity pathways in psoriasis.1,2 Data indicating that intrinsic alterations of keratinocytes are necessary to induce psoriasis were obtained firstly from studies using the severe combined immunodeficiency (SCID) mouse xenograft model.3 The injection of autologous immunocytes into the dermis of transplanted mice induced psoriasis only in prelesional symptomless skin of psoriatic patients and not in skin from healthy volunteers. However, the demonstration that endogenous defects in keratinocytes are pathogenetically relevant for psoriasis has been obtained recently using mice with engineered epidermal phenotypes. In particular, transgenic animals overexpressing the transcription factor signal transducer and activator of transcription 3 (STAT3) or lacking the inhibitor of nuclear factor (NF)-B kinase 2 (IKK2) in the epidermis, developed skin lesions that closely resembled human psoriasis.4,5 Similarly, the abrogation of JunB/activator protein 1 (AP-1) in keratinocytes triggered in

582 mice a skin phenotype with the histologic hallmarks of psoriasis, including marked hyperplasia of the epidermis accompanied by a dense dermal infiltrate of inflammatory cells.6 The development of psoriatic lesions in mice with the epidermal deletion of STAT3 depended on the presence of activated T cells, whereas the inflammatory responses occurring in the skin of IKK2 transgenic mice were mediated by TNF-. Therefore, it is clear that an intrinsically dysregulated interrelation between keratinocytes and cells of both innate and acquired immunity is a key step in the pathogenesis of psoriasis (Fig. 1). In this review, we will focus on the multiple roles of keratinocytes in initiating, sustaining, and amplifying the inflammatory processes associated with psoriasis. These processes ultimately imply

C. Albanesi et al. local recruitment and activation of pathogenetic leukocytes, which finally induces the psoriatic phenotype. More important, keratinocyte intrinsic alterations in the response to T cellderived signals are also essential for their aberrant hyperproliferation and differentiation, critical hallmarks of psoriatic skin.

Psoriatic keratinocytes as activators of pathogenetic T lymphocytes

Psoriasis lesional skin shows a prominent presence of inflammatory cells localized both in the papillary dermis and

Fig. 1 Pathogenic mechanisms operating in psoriasis. Type 1 cytokines, mainly represented by IFN-, are locally produced by infiltrating Th1, Tc1, and natural killer cells and are responsible for the activation of resident skin cells, in particular keratinocytes, in psoriatic skin. They respond to cytokines with a stereotyped set of genomic responses leading to synthesis of inflammatory mediators. Keratinocyte-derived chemokines, cytokines, and membrane molecules have a major role in continuing recruitment of leukocyte into inflammatory sites. Because of their intrinsic defects, psoriatic keratinocytes respond aberrantly to cytokines and show altered intracellular signaling pathways. The uncontrolled hyperproliferation and differentiation observed in psoriatic skin could derive from a dysregulated production of tissue growth factors and regulators, such as TGF-, KGF, amphiregulin, GM-CSF, FGF-10, IL-19, and IL-20 produced by keratinocytes and fibroblasts. It is still unclear if psoriatic keratinocytes produce autoantigens, such as keratin (K)17 and K13, able to induce clonal T-cell responses. Finally, the inflammatory cytokine milieu also influences the immune functions of fibroblasts and endothelium, with the latter being critical for leukocyte trafficking and extravasation.

Resident skin cells in psoriasis in the epidermis.1 Imunophenotyping T cells in psoriasis showed that they are mainly activated memory T cells expressing HLA-DR, CD25, CD27, and the cutaneous lymphocyte-associated antigen (CLA). Both CD4+ and CD8+ T-cell subsets are present in psoriatic skin lesions, with CD8+ cells predominant in the epidermis.1 Psoriasis is generally thought to be a type 1 T-cell disease because interfereron (IFN-)producing T cells predominate in lesional skin and in the peripheral circulation, and type 1 responsesustaining mechanisms (involving interleukin [IL]-23 more than IL-12) are locally present.7,8 Although it was shown that psoriatic T cells in vivo bear preferentially certain T-cell receptors,1 the causative antigen responsible for T-cell activation in psoriasis remains unknown. Some evidence indicates that the exposure of altered autoantigens by keratinocytes could be directly responsible for the activation and expansion of certain T-cell subpopulations in psoriatic skin.1 Part of such autoantigens would derive from psoriasis-associated alleles of genes residing in specific genomic regions. Several genetic association and linkage studies demonstrated that the most important psoriasis susceptibility locus is PSORS1, near HLA-C in chromosome 6p.21.9 This region is characterized by strong linkage disequilibrium and contains the corneodesmosin gene, an attractive candidate for psoriasis susceptibility based on its putative biological function in keratinocyte adhesion, and HLA-Cw6, an established marker for psoriasis susceptibility, which may be involved in the recognition of foreign antigens by HLA-Cw6restricted CD8+ T cells. Alternatively, it might lead to different or preferential binding of heterologous or autologous antigens, with subsequent recognition by CD8+ T cells. A keratinocyte-derived candidate autoantigen is keratin 17.10 Patients with active psoriasis have an increased frequency of circulating Th1 cells reacting to peptides from keratin 17 that shares ALEEAN aminoacidic sequence with the streptococcus M-protein.10 Recently, using a new approach termed SErological identification of Recombinant EXpressed antigens (SEREX), new autoantigens were found in the serum of patients with psoriasis.11 Keratin 13, heterogeneous ribonucleprotein-A1, and a previously uncharacterized protein, FLJ00294, were identified by SEREX as representative antigens in psoriatic patients, although autoreactivity for these proteins was also detected in control subjects without psoriasis.11 Finally, keratinocytes could be indirectly responsible for the activation of pathogenetic T cells through the exposure of viral or bacterial products. For example, a significant prevalence of epidermodysplasia verruciformisassociated human papillomavirus 5 (HPV-5) DNA and antibodies to HPV-5 viruslike particles L1 has been identified in psoriasis. It has been hypothesized that induction of epidermal proliferation in psoriasis by generic stimuli initiates the life cycle of HPV-5, which in turn expresses early (E6/E7) and late (L1) viral proteins, responsible for keratinocyte proliferation and Tcellmediated responses, respectively.12 Streptococcal infections are also frequently associated to psoriasis, and

583 streptococcal superantigens could be presented to T cells by binding major histocompatibility complex (MHC) class II molecules expressed by lesional keratinocytes. MHC class II molecule expression by keratinocytes in psoriasis is determined primarily by IFN- released locally by infiltrating type 1 CD4+ and CD8+ T cells and natural killer cells.13,14 Presentation of bacterial products by MHC class II+ keratinocytes fits with the presence in psoriatic skin of clonal T cells bearing a restricted array of Tcell receptors. Interestingly, the putative psoriatic antigens were assumed to be keratinocyte proteins that share structural homologies with streptococcal proteins and, thus, induce cross-reactive responses of antibacterial T cells against skin components.15

Aberrant growth and differentiation of keratinocytes in psoriasis

The histoarchitecture and function of the epidermis depend on a well-controlled balance between keratinocyte proliferation and differentiation. This balance is perturbed during psoriasis where an increased epidermal turnover is observed, with keratinocytes oriented toward a robust regenerative program similar to that observed during response to injury and wounding. Studies analyzing different markers of cell differentiation and cell cycle revealed an augmented number of -integrin+ keratin (K)1/K10 proliferating cell nuclear antigen (PCNA) keratinocytes in psoriatic skin, thus sustaining the hypothesis that there is an increase in the stem cell population in psoriasis.16 In parallel, it was suggested that it is the pool of dividing suprabasal keratinocytes, also known as transient amplifying cells, that is enlarged in psoriatic skin.17 Evidence of an aberrant expression of apoptosis-related molecules and senescenceassociated signals further complicates the understanding of the diverse processes going on in psoriatic skin.18,19 Control of keratinocyte growth is mediated by a variety of growth factors, including insulin-like growth factor, keratinocyte growth factor (KGF), transforming growth factor (TGF-) and amphiregulin, which stimulate basal cell proliferation in an autocrine fashion, and members of the inhibitory TGF-, which are produced by suprabasal cells.20,21 All these pathways are altered in psoriasis and the role of KGFs in the genesis of epidermal hyperplasia has been confirmed in various transgenic mouse models.22-24 Overexpression of KGF in the basal epidermal layer of transgenic mice resulted in epidermal hyperplasia and early papilloma formation, demonstrating that KGF induces proliferation but not differentiation of keratinocytes.22 These findings correlate with in vitro results showing the ability of KGF to inhibit keratinocyte differentiation and apoptosis.25 Similarly, targeted overexpression of TGF- or amphiregulin to the epidermis of transgenic mice elicits hyperplasia and hyperkeratosis, suggesting a relevant role in controlling epidermal thickness and turnover in psoriasis.23,24

584 Interestingly, the use of a humanized monoclonal antibody capable of neutralizing human amphiregulin effectively reverses the epidermal hyperplasia of psoriatic skin transplanted onto SCID mice.26 With regard to the involvement of negative regulators of growth and proliferation in psoriasis, some observations indicate a reduced TGF- expression and TGF-mediated signaling in psoriatic plaques. In particular, all the 3 isoforms of TGF- and their receptors, TGF- receptors I and II, are diminished in psoriasis, and the overexpression of latent TGF-1 in transgenic epidermis resulted in a severe psoriasis-like skin disorder.27-29 To make things more complicated, a variety of other cytokines that also act as autocrine growth stimulators of keratinocyte proliferation are elevated in psoriasis. These includes IL-6 and CXCL8/IL-8, with the latter being involved also in the massive recruitment of neutrophils in psoriatic skin.30 Recently, IL-19 and IL-20 overexpression in psoriasis has been correlated with keratinocyte proliferation and inflammation, and the analysis of single nucleotide polymorphisms in these genes revealed the existence of haplotypes associated with an increased risk for psoriasis.31,32 All the above-described growth factors possibly involved in the increased epidermal proliferation in psoriasis might come from a variety of cells other than keratinocytes themselves. However, many studies in the past have indicated that T cells are the primary inducers of keratinocyte hyperproliferation in psoriasis. In fact, supernatants from lesional skinderived CD4+ T cells (activated with anti-CD3 and fibronectin) transformed -integrin+ K1/K10 PCNA stem cells of patients with psoriasis, but not stem cells of healthy subjects, into PCNA+ active cycling cells.33 T cellderived supernatants were found to contain high levels of granulocytemonocyte colonystimulating factor (GM-CSF) and IFN-, low levels of IL-3 and TNF-, and variable IL-4 level, but among these cytokines only IFN- influenced the proliferation of psoriatic stem cells. In addition, IFN- injection into prelesional psoriatic skin causes keratinocyte proliferation and plaque development.34 Considering that IFN- is a potent antiproliferative cytokine and inducer of squamous differentiation, the latter findings represent an intriguing paradox. This discrepancy can be explained by a fundamental defect in the response of psoriatic keratinocytes to IFN-.35,36 At the molecular level, the diminished sensitivity of psoriatic keratinocytes to IFN- results in a reduced activation of the transcription factors IRF-1 and STAT1, whose correct functioning guarantees proper control of growth, differentiation, and apoptotic processes.35 Another possible explanation for the reduced effect of IFN- on psoriatic keratinocytes can reside in the altered localization and expression level of the IFN- receptor complex in the epidermis of psoriatic compared with healthy skin.37 Finally, the -helix coiled coil rod homologue gene, mapping in the PSORS1 locus between HLA-C and corneodesmosin genes, has been found to be involved in keratinocyte proliferation and response to IFN-, and to have a psoriasis-associated allele (HCR*WWCC).38

C. Albanesi et al.

Psoriatic keratinocytes are a reservoir of inflammatory mediators

The massive presence of activated type 1 T cells and other leukocyte populations in psoriatic lesions determines the establishment of a cytokine milieu, mainly represented by IFN-, TNF-, IL-23, and IL-17.8,39 Under the influence of these proinflammatory cytokines, keratinocytes express a plethora of mediators, thereby contributing to amplifying the inflammatory response.13 Various studies have documented a strong chemokine expression in psoriatic keratinocytes of lesional skin, and keratinocyte production of chemokines may contribute relevantly to the recruitment of the inflammatory infiltrate.40 Specifically, CXCL8/IL-8 and related chemokines are responsible for the intraepidermal collection of neutrophils.41 CCL2/MCP-1, CCL5/RANTES, CXCL10/IP-10, and other CXCR3 ligands attract predominantly monocytes and Th1 cells,42,43 whereas CCL20/MIP3 recruits immature Langerhans cells, dendritic cells, and CLA+ T cells.44,45 In line with these observations, T cells bearing CCR4, CXCR3, and CCR6 receptors are well represented in psoriatic skin lesions.46 CCL13/MCP-4 is also strongly expressed in the basal layers of the psoriatic epidermis, and together with CCL20/MIP-3 can direct the traffic of immature dendritic cells.46 CCL27/CTACK is abundantly present in basal and suprabasal keratinocytes of psoriatic lesions as well as in the dermis, together with a high number of CCR10+ T cells.47 Consistent with the Th1dominated immunity, CCR10 is preferentially expressed by skin-homing CLA+ memory T cells secreting TNF- and IFN-, but minimal IL-10 and IL-4 upon activation.48 In a recent comparison of the inflammatory gene expression pattern between psoriasis and atopic dermatitis skin lesions performed with microarray technology, CCL20/MIP-3 transcripts were found much more strongly expressed in psoriasis than in atopic dermatitis, whereas the opposite held true for CCL13/MCP-4 and CCL27/CTACK.49 In addition, CCL4/MIP-1, which is active toward CCR1- and CCR5bearing Th1 cells, immature dendritic cells, and monocytes, is strongly expressed in psoriatic lesions.49 Moreover, nitric oxide (NO) generation is decreased in psoriatic lesions, and we could observe that an NO releaser reduces the epidermal expression of CXCL10/IP-10, CCL5/RANTES, and CCL2/ MCP-1 and the presence of CD14+ and CD3+ cells infiltrating the psoriatic skin.50-52 In addition, NO donors efficiently opposed NF-B and STAT-1 binding activity associated with IFN- and TNF- stimulation in psoriatic keratinocytes.50 These results define NO donors as potential drugs for the treatment of psoriasis. In addition, the clinical efficacy of targeted immunomodulatory therapy for psoriasis, such as IL-10 and dimethylfumarate, is associated with a down-regulation of chemokine production by keratinocytes.53,54 In particular, administration of IL-10 to patients with chronic plaque psoriasis inhibits the expression of CXCL8/IL-8, its receptor CXCR2, and its inducer IL-17.55

Resident skin cells in psoriasis Consistently, dimethylfumarate suppresses IFN-induced production of CXCL1/Gro-, CXCL8/IL-8, CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC in keratinocytes and peripheral blood mononuclear cells.56 In addition, the cytokine production system is heavily deteriorated in psoriatic keratinocytes. Profound alterations in the IL-1 IL-1R axis have been detected in lesional psoriatic skin.57,58 In general, IL-1 was either decreased or unaffected, whereas higher levels of IL-1 messenger RNA and protein were measured. Both the intracellular and the soluble isoform of the IL-1 receptor antagonist are increased in psoriatic lesions. Similarly, messenger RNA expression and protein levels of the IL-1-RII decoy receptor are augmented in psoriatic skin lesions, whereas the signaling type I receptor is relatively unaffected. The latter observations may suggest the activation of inefficient loops of the negative regulation of the IL-1 system in psoriasis. Consistent with an important role of IL-1 is the observation that transgenic expression of IL-1 and the type I receptor in the skin results in pathologic abnormalities resembling those found in psoriasis. 59 Lesional keratinocytes are also strong producers of IL-15, which not only appears critical in the promotion of T cell and monocyte activation and, hence, in the maintenance of the local proinflammatory milieu, but also in the keratinocyte self-protection from apoptosis. 60 IL-18, known to be involved in the regulation of Langerhans cell migration, is strongly up-regulated in the epidermis of psoriatic skin and hints at a relevant role of this cytokine in disorders mediated by prevalent IFN-producing T lymphocytes.61 Finally, keratinocytes are an important source of angiogenic factors, including vascular endothelial cell growth factor, considered as a key cytokine driving angiogenesis in psoriasis.62

585 sion. This paracrine regulation of KGF expression by PTHrP might at least partially explain the epidermal atrophy seen in the skin of PTHrP-null mice, and correlates well with the epidermal hyperplasia seen in transgenic mice overexpressing PTHrP in basal keratinocytes.65 The lack of phenotypic abnormalities in the epidermis of KGF-deficient mice, however, points to compensatory mechanisms by other growth factors, such as fibroblast growth factor (FGF)-10.66 In addition to FGF family members, GM-CSF also plays a particularly important role in the fibroblast-driven regulation of keratinocyte proliferation. GM-CSF expression is induced in dermal fibroblasts cultured in the presence of keratinocytes, and keratinocyte-derived IL-1 appears to be responsible for this induction. 63 More important, psoriatic fibroblasts are also in the hyperactive state in terms of production of extracellular matrix proteins and altered proliferative response to serum factors. A hallmark of psoriatic skin not yet described in this review is the substantial transformation of the local microvascular system, showing dilatation and tortuosity of capillaries, increased permeability, and high endothelial venule formation.1 Microvessels in the papillary dermis show increased endothelial surface areas and exhibit endothelial cell proliferation. This capillary dilatation may help nourish the hyperproliferating skin and allow massive Tcell extravasation and trafficking. The distinctive activated phenotype of lesional endothelial cells is believed to play a central role in the pathogenesis of psoriasis and is determined by the expression of a variety of membrane and soluble factors mainly responsible for T-cell recruitment in the skin.67 A key step in trafficking of T cells into inflamed skin is the interaction between leukocyte functionassociated antigen 1 on T cells and intercellular adhesion molecule 1 (ICAM-1) on endothelium. The pathogenetic relevance of ICAM-1 on psoriatic endothelial cells can be deduced indirectly considering the strong efficacy of biological therapy with Efalizumab, a humanized monoclonal antibody to CD11a, which is a component of leukocyte functionassociated antigen 1 on T cells.68 Determinant is also the endothelium expression of certain chemokines involved in the arrest of circulating T lymphocytes at inflammatory sites. Upon exposure to inflammatory signals, mainly represented by TNF- and IL-1, endothelial cells express a broad array of chemokines, including CCL20/MIP-3, CXCL12/SDF-1, CCL21/SLC, CCL17/TARC, CCL2/MCP-1, CXCL10/IL-8, CCL5/RANTES, CXCL1/Gro-, and CCL4/MIP-1.69 In particular, CCL17/TARC has been detected in venules of psoriatic skin and determines the integrin-dependent adhesion of CCR4+ T cells to endothelium.70 Moreover, CCL20/ MIP-3 is critical for the arrest of CCR6+ T lymphocytes on activated dermal endothelium, suggesting a role for this chemokine in T-cell recruitment in psoriatic skin where CCR6 is up-regulated.71 Finally, CXC3L1/fractalkine is expressed on the membrane of endothelial cells and modulated by inflammatory signals and cytokines. The fractalkine/ CX3CR1 axis can be part of an amplification circuit of

Heterogeneous functions of other skin resident cells in psoriasis

Although intrinsic alterations in keratinocytes are crucial for the development of psoriatic lesions, a deregulated function of other resident skin cells, such as fibroblasts and endothelial cells, may also contribute to the pathogenesis of psoriasis. Epidermal-dermal cell interaction is a determinant for the maintenance of the psoriatic phenotype because it guarantees the local production of growth factors and cytokines stimulating keratinocyte proliferation.17 An important paracrine loop operating between keratinocytes and fibroblasts that culminates with keratinocyte proliferation is triggered by IL-1.63 A study performed on cocultures of keratinocytes and fibroblasts demonstrated that IL-1 and IL1 neutralization and IL-1 receptor antagonist significantly reduced keratinocyte growth through the abrogation of KGF production by fibroblasts.64 However, IL-1 is unlikely to be the only regulator of KGF production by fibroblasts, and indeed other keratinocyte-derived factors, such as parathyroid hormonerelated protein (PTHrP), induce KGF expres-

586 polarized type 1 responses, as suggested by the higher and selective expression of this chemokine in psoriasis.72

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2. Gisondi P, Gubinelli E, Cocuroccia B, et al. Targeting tumor necrosis factor-alpha in the therapy of psoriasis. Curr Drug Targets Inflamm Allergy 2004;3:175-83. 3. Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes induces psoriasis. J Clin Invest 1996;98:1878-87. 4. Sano S, Chan KS, Carbajal S, et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med 2005;11:43-9. 5. Pasparakis M, Courtois G, Hafner M, et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 2002;417:861-6. 6. Zenz R, Eferl R, Kenner L, et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 2005; 437:369-75. 7. Austin LM, Ozawa M, Kikuchi T, et al. The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999;113:752-9. 8. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004;199:125-30. 9. Trembath RC, Clough RL, Rosbotham JL, et al. Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. Hum Mol Genet 1997;6:813-20. 10. Gudmundsdottir AS, Sigmundsdottir H, Sigurgeirsson B, et al. Is an epitope on keratin 17 a major target for autoreactive T lymphocytes in psoriasis? Clin Exp Immunol 1999;117:580-6. 11. Jones DA, Yawalkar N, Suh Ki-Y, et al. Identification of autoantigens in psoriatic plaques using expression cloning. J Invest Dermatol 2004;123: 93-100. 12. Majewski S, Jablonska S. Possible involvement of epidermodysplasia verruciformis human papillomaviruses in the immunopathogenesis of psoriasis: a proposed hypothesis. Exp Dermatol 2003;12:721-8. 13. Albanesi C, Scarponi C, Giustizieri ML, et al. Keratinocytes in inflammatory skin diseases. Curr Drug Targets Inflamm Allergy 2005; 4:329-34. 14. Ottaviani C, Nasorri F, Bedini C, et al. CD56brightCD16() NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation. Eur J Immunol 2006;36:118-28. 15. Prinz JC. Psoriasis vulgarisa sterile antibacterial skin reaction mediated by cross-reactive T cells? An immunological view of the pathophysiology of psoriasis. Clin Exp Dermatol 2001;26:326-32. 16. Bata-Csorgo Z, Hammerberg C, Voorhees JJ, et al. Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis. J Exp Med 1993;178:1271-81. 17. McKay IA, Leigh IM. Altered keratinocyte growth and differentiation in psoriasis. Clin Dermatol 1995;13:105-14. 18. Iizuka H, Takahashi H, Honma M, et al. Unique keratinization process in psoriasis: late differentiation markers are abolished because of the premature cell death. J Dermatol 2004;31:271-6. 19. Nickoloff BJ, Ben-Neriah Y, Pikarsky E. Inflammation and cancer: is the link as simple as we think? J Invest Dermatol 2005;124:x-xiv. 20. Piepkorn M, Pittelkow MR, Cook PW. Autocrine regulation of keratinocytes: the emerging role of heparin-binding, epidermal growth factorrelated growth factors. J Invest Dermatol 1998;111: 715-21. 21. Glick AB, Kulkarni AB, Tennenbaum T, et al. Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc Natl Acad Sci U S A 1993;90:6076-80. 22. Guo L, Yu QC, Fuchs E. Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice. EMBO J 1993;12:973-86.

Conclusions
Activated T cells are necessary for the development and persistence of psoriatic lesions, but psoriasis cannot be explained solely on the basis of T-cell activation. In fact, infiltration of IFN-producing type I cells in the epidermis is a common response to intrinsic or extrinsic antigens in persons in whom psoriasis never develops. Whether this paradox can be explained by the existence of a unique subgroup of cytokines produced by psoriatic T cells or whether resident skin cells from psoriatic patients have an aberrant response to cytokines or other effector molecules is not definitely demonstrated. In this review we have provided much evidence revealing that intrinsic multigenic alterations in resident skin cells, in particular keratinocytes, are essential for the development of psoriasis. The enhanced and altered expression of certain inflammatory mediators as well as the deregulation of proliferative processes in the epidermis of psoriatic skin could be the result of a genetic predisposition explicated mainly through a compromised control of gene expression. The large number of dysregulated genes observed in psoriatic keratinocytes allows one to believe that the genetic aberration in psoriasis is quite basic, that is, it is proximal to the common element in the cascade of inflammatory events. Indeed, many intracellular signaling pathways have been found altered in psoriatic keratinocytes, including STAT1-, STAT3-, NF-B, AP-1, p38-, and Erk1/2 kinaseactivated pathways.73,74 Nevertheless, it is also possible that the natural brakes involved in the suppression of inflammatory responses and/or growth signals are compromised in psoriatic skin cells. On this matter, we identified the suppressor of cytokine signaling 1 (SOCS1) and SOCS3 proteins as potent negative regulators of IFN- signaling in keratinocytes.75 Overexpression of SOCS1 and SOCS3 in keratinocyte clones abrogated the IFN-induced expression of ICAM-1 and MHC class II molecules and release of CXCL10/IP-10, CXCL9/Mig, and CCL2/MCP-1 chemokines by inhibiting STAT1 and STAT3 activities. These findings identify SOCS1 and SOCS3 molecules as new potential molecular targets for those IFN-dependent skin diseases where proinflammatory mediators are aberrantly expressed by keratinocytes. Regulation of the inflammatory events initiated or perpetuated by keratinocytes could represent an important strategy for the treatment of psoriasis and other chronic inflammatory skin diseases.

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