Resident skin cells in psoriasis: a special look at the pathogenetic functions of keratinocytes
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
References (75)
- 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) - et al.
Identification of autoantigens in psoriatic plaques using expression cloning
J Invest Dermatol
(2004) - et al.
Altered keratinocyte growth and differentiation in psoriasis
Clin Dermatol
(1995) - et al.
Inflammation and cancer: is the link as simple as we think?
J Invest Dermatol
(2005) - et al.
Autocrine regulation of keratinocytes: the emerging role of heparin-binding, epidermal growth factor–related growth factors
J Invest Dermatol
(1998) - et al.
Keratinocyte growth factor inhibits cross-linked envelope formation and nucleosomal fragmentation in cultured human keratinocytes
J Biol Chem
(1996) - et al.
Amphiregulin is required to maintain the psoriatic phenotype of human skin grafts on severe combined immunodeficient mice
Am J Pathol
(2005) - et al.
Downregulation of TGFbeta isoforms and their receptors contributes to keratinocyte hyperproliferation in psoriasis vulgaris
J Dermatol Sci
(2003) - et al.
Expression of interferon-gamma receptors in normal and psoriatic skin
J Invest Dermatol
(1992) - et al.
Immunological functions of non-professional antigen-presenting cells: new insights from studies of T-cell interactions with keratinocytes
Immuno Today
(1994)
MCP-1 mRNA expression in basal keratinocytes of psoriatic lesions
J Invest Dermatol
Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis
J Allergy Clin Immunol
Nitric oxide donors suppress chemokine production by keratinocytes in vitro and in vivo
Am J Pathol
Arginase 1 overexpression in psoriasis: limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation
Am J Pathol
Explaining decreased nitric oxide production in psoriatic lesions: arginase 1 overexpression versus calcitonin gene-related peptide
Am J Pathol
Dimethylfumarate for psoriasis: more than a dietary curiosity
Trends Mol Med
Response of psoriasis to interleukin-10 is associated with suppression of cutaneous type 1 inflammation, down-regulation of the epidermal interleukin-8/CXCR2 pathway and normalization of keratinocyte maturation
J Invest Dermatol
Exacerbated and prolonged allergic and non-allergic inflammatory cutaneous reaction in mice with targeted interleukin-18 expression in the skin
J Invest Dermatol
Paracrine regulation of keratinocyte proliferation and differentiation
Trends Cell Biol
Parathyroid hormone–related protein is a positive regulator of keratinocyte growth factor expression by normal dermal fibroblasts
Mol Cell Endocrinol
Defective terminal differentiation and hypoplasia of the epidermis in mice lacking the Fgf10 gene
FEBS Lett
Psoriasis
Lancet
Psoriasis: dysregulation of innate immunity
Br J Dermatol
Targeting tumor necrosis factor-alpha in the therapy of psoriasis
Curr Drug Targets Inflamm Allergy
Dermal injection of immunocytes induces psoriasis
J Clin Invest
Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model
Nat Med
TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2
Nature
Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins
Nature
Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris
J Exp Med
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
Is an epitope on keratin 17 a major target for autoreactive T lymphocytes in psoriasis?
Clin Exp Immunol
Possible involvement of epidermodysplasia verruciformis human papillomaviruses in the immunopathogenesis of psoriasis: a proposed hypothesis
Exp Dermatol
Keratinocytes in inflammatory skin diseases
Curr Drug Targets Inflamm Allergy
CD56brightCD16(−) NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation
Eur J Immunol
Psoriasis vulgaris—a sterile antibacterial skin reaction mediated by cross-reactive T cells? An immunological view of the pathophysiology of psoriasis
Clin Exp Dermatol
Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis
J Exp Med
Unique keratinization process in psoriasis: late differentiation markers are abolished because of the premature cell death
J Dermatol
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2021, Autoimmunity ReviewsCitation Excerpt :Psoriasis is a chronic inflammatory skin disease mediated by both innate and adaptive immune responses. The disease is characterized by incomplete, defective basal keratinocyte differentiation induced by an inflammatory cascade in the dermis involving dendritic cells, macrophages, mast cells, and T cells (Fig. 1d) [61]. Parallels have been drawn between the etiopathomechanism of psoriasis and vitiligo [62–64], which has contributed to a rich history of therapeutics repurposed from psoriasis to vitiligo, including light therapies [65–67].