Elsevier

Clinics in Dermatology

Volume 25, Issue 6, November–December 2007, Pages 581-588
Clinics in Dermatology

Resident skin cells in psoriasis: a special look at the pathogenetic functions of keratinocytes

https://doi.org/10.1016/j.clindermatol.2007.08.013Get rights and content

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by exaggerated keratinocyte proliferation. Current paradigm indicates that psoriasis is driven by T cell–mediated 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 cell–derived 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.

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 anti–tumor necrosis factor α (TNF-α) therapies are highly effective suggests the presence of pathologic activation of innate 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)-κB 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 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-α. 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 local recruitment and activation of pathogenetic leukocytes, which finally induces the psoriatic phenotype. More important, keratinocyte intrinsic alterations in the response to T cell–derived signals are also essential for their aberrant hyperproliferation and differentiation, critical hallmarks of psoriatic skin.

Section snippets

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 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

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 β-integrin+ keratin

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-γ, TNF-α, 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

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

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-γ–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

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