Journal of Dermatological Science
Volume 65, Issue 1 , Pages 4-11, January 2012

Chemokine receptors in the pathogenesis and therapy of psoriasis

  • Tomotaka Mabuchi

      Affiliations

    • Department of Dermatology, Medical College of Wisconsin, WI, USA
    • Department of Dermatology, Tokai University School of Medicine, Kanagawa, Japan
    • Corresponding Author InformationCorresponding author at: Department of Dermatology, Tokai University School of Medicine, 143, Shimokasuya, Isehara, Kanagawa 259-1193, Japan. Tel.: +81 463 93 1121; fax: +81 463 93 9387.
    • ,
  • Timothy W. Chang

      Affiliations

    • Department of Dermatology, Medical College of Wisconsin, WI, USA
    • ,
  • Suzanne Quinter

      Affiliations

    • Department of Dermatology, Medical College of Wisconsin, WI, USA
    • ,
  • Sam T. Hwang

      Affiliations

    • Department of Dermatology, Medical College of Wisconsin, WI, USA

Received 6 October 2011; received in revised form 10 November 2011; accepted 14 November 2011. published online 16 December 2011.

Article Outline

Abstract 

Chemokine receptors are G-protein-coupled, seven-transmembrane-spanning surface receptors that play key roles in cell trafficking, cell motility, and survival. These receptors are activated by small molecular weight chemotactic cytokines called chemokines. Chemokine receptors and their corresponding chemokine ligands play roles in the migration and localization of normal T cells (and other cells) during physiological responses in inflamed or infected skin. In psoriasis, the chemokine receptor CCR6 is expressed on the Th17 cells and γδ T cells, which produce a variety of cytokines (IL17 and IL22 among others), that play a role in the immunological activation. CCR6 and its ligand, CCL20, are highly expressed in psoriatic skin lesion and CCR6 is essential for the development of the psoriasiform phenotype following IL23 injection in mouse skin. In this review, we focus on the roles of chemokine receptors, particularly of CCR6, in the pathogenesis of psoriasis and discuss chemokine receptors as novel therapeutic targets for psoriasis.

Keywords: Psoriasis, Chemokine receptors, CCR6, IL22, γδ T cells

 

Back to Article Outline

1. Introduction 

Psoriasis is a common, inflammatory, and proliferative disease of the skin. The prevalence of psoriasis is approximately 2–3% of the population worldwide [1]. When compared with Caucasian populations, Asian populations have a lower prevalence of psoriasis. The prevalence of psoriasis in Japan is approximately 0.02–0.1% [2]. The exact cause of psoriasis is unclear, but it is thought to be a multifactorial disease triggered by both genetic and environmental factors such as trauma, drugs, infection, alcohol, smoking and stress.

A great deal of evidence that elucidate the pathogenesis of psoriasis has accumulated in the past 30 years. Until the 1970s, psoriasis was thought to be a disease of disordered keratinocyte proliferation and differentiation, which was based on the observation of epidermal hyperplasia seen both clinically and histologically. In the 1980s, the therapeutic success of cyclosporine A, a T cell-targeted immunosuppressant agent, for psoriasis [3], [4] shifted the paradigm from a view of psoriasis as a disease of disordered keratinocyte proliferation and differentiation to a view of psoriasis as a T cell-mediated inflammatory skin disease. Since the mid-2000s, the focus has moved from type 1 helper T (Th1)-cells as the culprit for the disease to type 17 helper T (Th17) cells, a view that has been strengthened by the success of the therapies targeted against TNFα and the Th17 pathways.

Back to Article Outline

2. Clinical and histologic features of psoriasis 

Psoriasis can be subdivided into at least four different clinical subtypes: guttate, inverse, palmoplantar and plaque psoriasis. Each subset, while organized under the overriding diagnosis of psoriasis, is unique with its own anatomic predilections, response to therapy, and, potentially, genetic signature. Guttate psoriasis presents clinically with small, scattered, scaly pink to red, papules and plaques, which have the potential to involve the majority of the skin surface area. A preceding streptococcal infection often incites the flare of guttate psoriasis. Inverse psoriasis also can be exacerbated by streptococcal infection, particularly within fissures of the gluteal cleft. Inverse psoriasis involves the folds of the body including the axillae, umbilicus, inguinal creases, and gluteal cleft. Inverse psoriasis, with an overlying streptococcal infection, can be difficult to eradicate if the infectious component is not addressed. This highlights how local factors and the associated cytokine milieu can influence the development of psoriatic lesions and alter response to treatment. In contrast, guttate psoriasis shows how a local infection can incite widespread cutaneous involvement; or perhaps, it shows how a systemic cytokine response permits a subset of cutaneous T cells to promote their psoriatic phenotype.

Plaque psoriasis, perhaps the most common variant of psoriasis, is typified by red, well demarcated plaques with white, silvery scale often involving the extensor elbows and knees. Recent research has shown that the epidermis and dermis are home to tens of millions of resident effector memory T cells [5]. It has also been shown that even after clinical resolution of psoriatic plaques, a genetic signature of psoriasis and its associated inflammatory state remains [6]. Suarez-Farinas et al. termed this state the “residual disease genomic profile”. These recent developments create a scientific link to a well known clinical fact that psoriasis often recurs in areas of previous involvement. The resident effector memory T cells may have a genetic tendency that, when provoked by environmental factors, quickly and reproducibly promote a psoriatic phenotype. Koebnerization, a well recognized phenomenon in psoriasis, may be explained by the resident T cell population reacting to a local change in cytokines produced by epidermal trauma. Palmoplantar psoriasis, one could argue, is continually fueled by Koebnerization, since the hands and feet by nature are constantly traumatized. Better understanding of the nuances of the individual genetic signatures, may in the future, provide more precise targets for treatment.

The histology of psoriasis is characterized by very typical changes within each level of the epidermis and dermis. The cornified layer has parakeratosis as well as collections of neutrophils at the junction of the cornified and granular layers, termed subcorneal pustules of Kogoj. The granular layer is often thinned or missing completely, and there is epidermal hyperplasia with regular elongation of the rete ridges. The suprapapillary plates are thinned, and the papillary dermis contains dilated, superficial vessels.

The T cell rich inflammatory infiltrate seen in psoriasis is often perivascular and interstitial in distribution. In psoriasis, studies have shown >90% of the T cell infiltrate expresses CC chemokine receptor 10 (CCR10), a receptor for the chemokine ligand, CCL27. Tumor necrosis factor (TNF)α upregulates CCL27 expression in keratinocytes in mice and humans and promotes effector memory T cell recruitment to the skin [7]. Since chemokines are likely to play an integral role in T cell recruitment and activation in psoriasis, CCL27 and other chemokines, notably CCL20, are being considered as possible therapeutic targets in psoriasis.

Chemokine receptors and their corresponding chemokine ligands play important roles in T cell-mediated inflammatory skin diseases, including psoriasis [8]. It is known that chemokine receptor-expressing immune cells (e.g. Th1 cells expressing CXCR3, and Th17 cells expressing the chemokine receptors CCR6 and CCR4) emigrate into inflamed psoriatic skin along chemokine gradients [8]. However, the mechanism of immune cells migration is still unclear. Homey et al. also showed that CXCL8, a neutrophil chemoattractant (chemokine), is significantly elevated in psoriatic skin when compared to normal skin by quantitative PCR. The latest reports suggest that CCR6, a biomarker of Th17 cells, is critically important for Th17 pathway activity. In this review, we focus on the roles of chemokine receptors, particularly of CCR6, in the pathogenesis of psoriasis and discuss chemokine receptors as novel therapeutic targets for psoriasis.

Back to Article Outline

3. Cellular, cytokine and chemokine networks in psoriasis 

3.1. Cytokine pathways in psoriasis 

Chemotactic cytokines (i.e., chemokines) represent a large group of small chemotactic proteins (generally 8–11kDa in size) that direct the movement of circulating leukocytes to sites of inflammation or injury [9]. Chemokines are grouped into four families (C, CC, CXC, and CX3C) based on the spacing of key cysteine residues near the N terminus of the protein [9]. To avoid confusing jargon and multiple investigator-specific names, the chemokines and their receptors are generally known by their systematic names, consisting of the family of the chemokine followed by the letter R for receptor or L for ligand and a number indicating their order of discovery. The CC and CXC families form the majority of known chemokines (currently ∼50).

Chemokines interact with cell-surface receptors, which are members of a large superfamily of seven-transmembrane domain, G-protein-coupled receptors [9]. So far, 20 chemokine receptors have been described [10]. Some chemokine receptors bind to multiple chemokines and vice versa, suggesting that certain redundancies exist in chemokine function. Binding of chemokines to their corresponding receptors results in activation of several downstream signaling pathways, including phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK), leading to diverse cellular processing including, actin reorganization, cell movement, and resistance to apoptosis [11], [12]. The expression of several chemokines/chemokine receptors is increased in psoriatic skin lesions when compared with uninvolved skin of psoriatic patients or the skin of healthy controls (Table 1).

Table 1. Chemokine receptors/chemokines associated with psoriasis.
Chemokine receptorLigandCellular originPutative functionsReferences
CCR2 Monocytes/macrophages in the dermis, especially around the dermal vesselsMonocytes/macrophages/dendritic cells trafficking Th1 cells trafficking[51]
CCL2 (MCP1)Basal keratinocytes [51], [75]
CCR4 Epidermal T cells
Dermal CD3+ lymphocytes
Peripheral blood mononuclear cells		Th1 and Th17 cells trafficking[54], [76], [77]
CCL17 (TARC)
CCL22 (MDC)		Keratinocytes
Dermal endothelium		 [54]
[54]
CCR5 Epidermal CD3+ T cells
Dermal macrophages		Monocytes/dendritic cells chemotaxis
Th1 cells chemotaxis		[52], [76]
CCL3 (MIP1α)Epidermis
Upper dermis		 [52], [53], [62], [63], [78]
CCL5 (RANTES)Keratinocytes (basal keratinocytes and scale)Eosinophils trafficking[52], [75]
CCR6 Epidermal T cells
Peripheral blood mononuclear cells (PBMCs)		Th17 cells trafficking[29], [77]
CCL20 (MIP3α, LARC)Suprabasal keratinocytes [29]
CCR10 Leukocytes in perivascular, subepidermal and intraepidermalCLA+ CD4+, and CD8+ T cells trafficking[7]
CCL27 (CTACK)Basal keratinocytes [7], [79], [80]
CXCR1 EpidermisNeutrophils chemotaxis
T cells chemotaxis
Keratinocyte hyperproliferation		[81], [82]
CXCL8 (IL8)aKeratinocytes of upper epidermis [61], [75], [83]
CXCR2 Suprabasal keratinocytesNeutrophils activation
T cells chemotaxis
Keratinocyte hyperproliferation		[82]
CXCL1 (GROα)Keratinocytes of upper epidermis
Vessel-associated cells in the papillary dermis		 [83]
CXCL8 (IL8)aKeratinocytes of upper epidermis [61], [75], [83]
CXCR3 Dermal CD3+ lymphocytes
Intra-epidermal CD8+ lymphocytes
Basal keratinocyte layer
Plasmacytoid DCs (pDCs)		Th1 cells trafficking pDCs trafficking[54], [58]
CXCL9 (Mig)Keratinocytes
Macrophages
Dermal microvascular endothelial cells		 [53], [54], [58]
CXCL10 (IP10)Keratinocytes [54], [58], [75], [79], [84]
CXCL11 (ITAC)Psoriatic skin lesion (unknown) [58]
CXCR6b –Leukocytes trafficking
Keratinocyte hyperproliferation		–
CXCL16Cytoplasm of keratinocytes of lower epidermal layer
Dermal capillary endothelial cells		 [85]
CX3CR1 Vascular endothelial cellsTh1 polarization[86]
CX3CL1 (fractalkine)Vascular endothelial cells [86]

aCXCL8 is a ligand for both CXCR1 and CXCR2.

bThe expression of CXCR6 in psoriatic lesion has not reported.

3.2. Th17 signaling and CCR6 in psoriasis 

Over the past 5 years, a major shift has occurred in our understanding of the role of different T cell subsets in psoriasis and other autoimmune diseases. While Th1 cells, producing interferon (IFN)γ were thought to play the principal role in the immune activation observed in psoriasis, both mouse and human data now indicate that Th17 cells, producing a variety of cytokines (interleukin (IL)17 and IL22 among others) that play an equal, if not greater role, in the immunological activation that occurs in psoriasis.

Th17 cells were identified as a novel type of effecter helper T cells in 2005 [13], [14]. Th17 cells are T cells that preferentially produce IL17, but not IFNγ or IL4 [15]. Transforming growth factor β (TGFβ), IL6, IL1β, IL21, and IL23 are key cytokines for the development of human Th17 cells from naïve T cells [15]. IL23, a key upstream player in the Th17 pathway, is an essential cytokine for the maintenance of Th17 cells and plays roles in multiple autoimmune processes, including psoriasis, arthritis, and autoimmune encephalitis [16]. IL23 is a heterodimeric cytokine that shares its p40 subunit with IL12 [17]. Ustekinumab (Stelara®), a therapeutic agent targeting the shared p40 component of IL23, has shown remarkable clinical efficacy in psoriasis [18], validating the role of Th17 cytokines in human psoriasis. Because ustekinumab blocks IL12 (a Th1 cytokine) as well as IL17, it is not possible to completely rule out the role of Th1 cells in psoriasis.

A great deal of data, however, indicates that the Th17 signaling pathway is a key mediator in the development and maintenance of psoriasis [16]. The number of Th17 cells and downstream effecter molecules, IL17A, IL17F, TNFα, and IL22 are increased in psoriatic skin lesions [16]. With narrow-band UVB (NB-UVB) treatment, cytokines of the IL23/IL17 pathway are normalized in psoriatic plaques [19]. In humans, IL17 plays a necessary role in the maintenance of the psoriatic phenotype as demonstrated by clinical studies showing the efficacy of antibodies (e.g. Secukinumab/AIN 457 and LY2439821) that are targeted specifically at IL17 [20], [21]. The roles of CD4+ T cells, including Th17 cells, in psoriasis are shown in Fig. 1.

  • View full-size image.
  • Fig. 1. 

    The roles of CD4+ T cell subtypes in psoriasis. Th cell subsets and Treg cells are differentiated from naïve T cells. Under conditions of healthy immune homeostasis, the activation of Th cells is, in part, regulated by Treg cells. T cell-mediated immune response is held in fine balance. In psoriasis, this balance is disrupted; pro-inflammatory cytokines produced from Th1 and Th17 cells dominate the cytokine profile. Solid arrows denote stimulatory actions, dashed arrows denote inhibitory actions.

In support of a role for the Th17 signaling pathway in psoriasis, it has been reported that intradermal IL23 injection into wild type (WT) mice results in psoriasis-like inflammatory changes such as parakeratosis, acanthosis, neutrophilic microabscess formation, and inflammatory infiltrates [22], [23], [24]. In this mouse model, intradermal injection of recombinant murine IL23 induced expression of Th17 cytokines IL17A, IL17F, and IL22 [22], [23], [24].

Circulating Th17 cells in adult human blood express CCR2, CCR4, CCR5, CCR6, and CXCR3 [25]. In particular, CCR6 has been described as a marker for Th17 cells both in human and murine T cells [8]. Recent studies have focused attention on the involvement of CCR6 in the pathogenesis of psoriasis. CCR6 was initially discovered on T cells [26] and immature dendritic cells (DCs) [27], [28]. Recently, several laboratories have shown that CCR6 plays an important role in the Th17 signaling pathway [10], and a variety of evidence suggests that CCR6 may play a critical role in psoriasis. First, circulating CCR6-expressing Th17 cells are increased both in psoriatic skin lesions and in the blood of psoriatic patients [29]. Moreover, CCR6 was shown to mediate adhesion of a subset of memory T cells to activated endothelial cells under physiologic shear stress conditions [30]. Lastly, current models suggest that IL23 produced by dendritic cells acts to sustain dermal CCR6-expressing Th17 cells which then produce IL22 as a major downstream effector of epidermal hyperplasia [31].

Hedrick et al. showed that CCR6 is essential for the development of the psoriasiform phenotype following IL23 injection in mouse skin [24]. In contrast to WT mice, Ccr6-deficient mice (Ccr6−/− mice) injected with IL23 showed neither psoriasis-like histological changes, including epidermal thickening, nor increased Il22 mRNA expression [24]. The lack of response of Ccr6-deficient mice to IL23 strongly suggests that the CCL20–CCR6 chemokine axis may be worth pursuing as a therapeutic target in psoriasis [32].

3.3. CCL20 in psoriasis 

CCR6 has only one known chemokine ligand, CCL20 [33]. CCL20 is constitutively expressed at low levels in normal human skin by epidermal keratinocytes and endothelial cells [33]. CCL20 production in keratinocytes and in endothelial cells, however, is strongly enhanced by proinflammatory cytokines, such as TNFα, IL1, IL17, and INFγ [30], [33]. In psoriatic skin lesions, CCL20 is highly expressed in the suprabasal layer of epidermis [24], [29]. CCL20 is the only CCR6-triggering chemokine and is not able to elicit a biological response through other known chemokine receptors [33]. β-Defensin also functions as CCR6 ligand, and β-defensin as well as other anti-bacterial peptides is strongly expressed in psoriasis [34]. The strict selectivity of CCL20 for CCR6 might be crucial in recruiting CCR6-expressing T cells into inflamed epidermis from dermis. Furthermore, the production of CCL20, which is enhanced by CCR6+ Th17 cell producing IL17, results in the recruitment of additional CCR6+ Th17 cells. The roles of chemokines/chemokine receptors including CCL20/CCR6 in psoriasis are shown in Fig. 2.

  • View full-size image.
  • Fig. 2. 

    The roles of chemokines and their receptors in psoriasis. CCR2-expressing monocytes and macrophages (Mϕ) migrate into epidermis via basal keratinocyte (KC)-derived CCL2, the CCR2 ligand. Circulating CCR4 and CXCR3-expressing Th1 cells move into epidermis from dermis via interaction with KC-derived CCL17 and/or CCL22, the CCR4 ligands, and CXCL9, CXCL10 and/or CXCL11, the CXCR3 ligands. CCR5-expressing CD3+ T cells and Mϕ migrate into epidermis through interaction with CCL3 and KC-derived CCL5, both CCR5 ligands. CCR6 has only one known chemokine ligand, CCL20. The selectivity of CCL20 for CCR6 allows recruitment of circulating CCR6-expressing cells, including Th17 cells, γδ T cells that express Th17 cytokines, and LCs into inflamed epidermis. CCR10-expressing cutaneous lymphocyte antigen (CLA)+, CD4+, and CD8+ T cells migrate into epidermis via KC-derived CCL27, the CCR10 ligand. CXCL8 is a common ligand for both CXCR1 and CXCR2 and is a potent chemoattractant for neutrophils. Plasmatoid dendritic cells (pDCs), which also express CXCR3, also traffic to inflamed epidermis. EC, endothelial cell; KC, keratinocyte; LC, Langerhans cell; Mϕ, macrophage; pDC, plasmatoid dendritic cell.

3.4. γδ T cells in psoriasis 

Although much is known about T cell receptor (TCR) αβ T cells in psoriasis, the role of unconventional T cells, including γδ T cells, is unclear. γδ T cells can be isolated from the synovial fluid of psoriatic patients [35] or from psoriatic skin [36]. Moreover, γδ T cells, including those expressing the cutaneous lymphocyte-associated antigen, have been reported to be present in greater numbers in guttate and plaque psoriasis lesions [37], [38]. Interestingly, peripheral γδ T cells express high levels of IL23R and respond to IL1β and IL23 by producing IL17 and IL22 [39]. Furthermore, a new study describes a motile population of dermal γδ T cells that express low-intermediate levels of γδ TCR, CCR6 and CXCR6, and IL17 [40].

In mouse skin, there are at least two distinct populations of γδ T cells [41]. Those expressing high levels of the γδ receptor are generally present in larger relative numbers even in unperturbed skin, show dendritic morphology (have been termed DETC), and express canonical T cell receptors (Vγ3 or 5, depending on the nomenclature used [42]). Using an IL23 skin injection model of psoriasiform dermatitis in mice as described above [22], [23], [24], we demonstrated that IL22, IL17A, and the IL23 receptor were highly enriched in a population of CCR6+, TCR γδ-low expressing (GDL) T cells that accumulated in the epidermis after IL23 injections [43]. GDL T cells were distinct from resident TCR γδ-high, Vγ3+, CCR6− T cells in the epidermis that did not change appreciably in numbers following IL23 injection. Large numbers of CCR6+ cells were detected at or above the level of the epidermal basement membrane by confocal microscopy five days after repeated IL23 injections at the same time that GDL cells increased in numbers in the epidermis. Lastly, TCR δ-deficient mice (lacking γδ T cells) exhibited decreased ear swelling and downregulated expression of IL22 and IL17A in the epidermis following IL23 injection. Together, our data suggest that a subset of γδ T cells play a critical role in IL23-mediated psoriasiform dermatitis although the relevance of γδ T cells in human psoriasis has yet to be proven at a functional level.

3.5. CCR6-expressing dendritic cells (DCs) in psoriasis 

In addition to T cells, Langerhans cells (LCs), which are the antigen-presenting DCs in epidermis [44], also express CCR6 [45] and are strongly attracted to CCL20 [46]. Komine et al. showed that the number of LCs (CD1a+CD11c+Langerin+ DCs) in lesional skin was increased compared with uninvolved skin, but was less compared with the perilesional skin of psoriatic plaques [47]. TNF/iNOS producing DCs (TIP DCs), also known as inflammatory DCs, are dermal DCs that produce both TNF and inducible nitric oxide synthase (iNOS) [44] and also play roles in development of psoriasis [48]. CD11c+ mature DCs from dermis of psoriatic skin lesions produce IL23 [49], is a key differentiation and growth factor for Th17 cells. TIP DCs from psoriatic skin lesion also produce IL20, which has the potential to directly activate keratinocyte proliferation [50].

Besides DCs, macrophages (Mϕ) infiltrate the dermis of psoriatic plaques and have been reported to express CCR2 in psoriatic lesions [51], CCR5 [52], and CXCL9 [53], [54]. Although there have been no reports that Mϕ express CCR6, it has been suggested that CCR6 signaling may be involved in the development of Mϕ lineage [55].

Rag1−/− mice, which lack both T cells and B cells, still showed psoriasiform phenotype and produced IL22 and IL17 initially following IL23 injection, demonstrating that T cells are not required initial responses to IL23 [24]. It is presumed that LCs, DCs, and Mϕ also have an influential role in the pathogenesis of psoriasis, possibly through expression of CCR6.

3.6. β-Defensin 2 in psoriasis 

In addition to CCL20, human β-defensin 2 (hBD2) has also been shown to elicit chemotaxis through CCR6 [34]. Defensins are small (3.5–4.5kDa in size), secreted anti-bacterial peptides. β-Defensins are primarily expressed by epithelial cells of the skin, kidney, and trachea–bronchial lining and possess a broad spectrum of anti-microbial activity against gram-positive and gram-negative bacteria, fungi, and viruses. HBD2 is highly expressed in lesional psoriatic epidermis [56]. Increased β-defensin genomic copy number is associated with psoriasis susceptibility in Dutch and German populations [57]. Jansen et al. showed that there was a significant correlation between serum hBD2 levels in psoriatic patients and the Psoriasis Area and Severity Index (PASI) and suggested that serum levels of hBD2 may be a useful surrogate marker for disease activity [56]. It is possible that increased hBD2 production in psoriasis acts in concert with CCL20 to attract requisite populations of CCR6 positive cells, including Th17 cells.

Back to Article Outline

4. Chemokine targets in psoriasis 

CXCR3 is expressed on dermal CD3+ lymphocytes and the ligands CXCL9, CXCL10, and CXCL11 (also known as Mig, IP10, and ITAC, respectively) are upregulated in psoriatic skin lesions [54], [58]. CXCR3 is involved in trans-endothelial migration of T cells into psoriatic dermis and mediates T cell trafficking to psoriatic epidermis [54]. The CXCR3 small molecule antagonist T487 was expected to provide symptomatic relief and block the progression of rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and psoriasis [59]. Although a phase II trial with T487 in psoriasis was performed in 2003 [60], there has been no further report of its utility in psoriasis.

CXCL8 (also known as IL8), one of the common ligands for CXCR1 and CXCR2, was initially identified as an anionic neutrophil-activating peptide (ANAP) in psoriatic scales [61]. CXCL8 represents a potent chemoattractant for neutrophils, which may be a factor in recruiting neutrophils into aggregations of neutrophils in the epidermis known as Munro abscesses. ABX-IL8 is a fully humanized neutralizing monoclonal antibody against CXCL8, that was evaluated in a phase II clinical trial for psoriasis. The development of ABX-IL8 was stopped due to a lack of efficacy in reducing PASI scores [59]. While the reason for this lack of patient benefit is unclear, this might be attributed to the presence of other redundant neutrophil-attracting CXCR2 ligands such as CXCL1, CXCL2, CXCL3, CXCL5, and CXCL6 [32].

CCL5 (also known as RANTES), one of the ligands for CCR5, has been shown to be highly expressed in psoriatic skin lesions [62], [63]. Tacalcitol, an active vitamin D3 analogue, inhibited CCL5 production in cultured normal epidermal keratinocytes [62]. Furthermore, CCR5 expression was significantly higher both in epidermal T cells and dermal macrophages, when comparing lesional psoriatic skin to non-lesional skin [52]. These results have suggested that CCR5 and CCL5 may play a role in the inflammatory cascade of psoriasis. However, in clinical trials the CCR5 inhibitor SCH51125 yielded neither clinical benefit nor significant differences in CCR5 expression. These clinical data suggest that CCR5 itself does not play a crucial role in the pathogenesis of psoriasis [52].

Although Hedrick et al. in their review suggest that CCR6 antagonists may be helpful in psoriasis based on multiple experimental data [32], there are no human therapeutic agents targeting CCR6/CCL20 for psoriasis currently in trials. Such an agent might be useful for other Th17-mediated autoimmune processes since an anti-CCR6 antibody reduced the severity of collagen-induced arthritis, a model for rheumatoid arthritis [64]. While no small molecule inhibitors of CCL20 or CCR6 have yet been described, new in silico techniques [65] may soon allow the rational design of drugs that directly bind to and antagonize CCL20 or CCR6. Such small molecule antagonists having micromolar affinity have already been discovered by such techniques for the chemokine CXCL12 [66].

Back to Article Outline

5. Other novel therapeutics for psoriasis that target Th17 cytokine signaling and lymphocyte migration 

The Th17 pathway described above signals through a network of intermediaries and partner proteins such as JAKs that affect cytokine release, keratinocyte proliferation, and lymphocyte migration. Three additional therapeutic targets that represent key intermediaries in Th17-mediated inflammatory processes or lymphocyte trafficking are described below in order to give a broader perspective of alternative targets that may be effective in psoriasis.

5.1. Janus Kinase inhibitors 

Janus Kinases (JAKs) in partnership with STAT proteins (e.g. STAT3) are important upstream conduits for signal transduction of inflammatory cytokines in psoriasis [67]. Targeting of upstream kinases has been seen to be more efficacious than targeting of the downstream counterparts [68]. CP-690 550 (tofacitinib) is an oral JAK-1,3 specific inhibitor. JAK-3 is critical for signal transduction of IL2, IL4, IL7, IL9, IL15, and IL21 in immune cells, which leads to lymphocyte activation and proliferation [69]. JAK-3-knockout mice have shown T and B-lymphocyte and natural killer cell defects, with no observation of other defects. Therefore, JAK-3 selective inhibitors have potential to mediate modulation of immune cells without significantly altering other organ systems [68]. Another specific inhibitor being investigated is INCB18424, which targets JAK-1,2. There have been concerns with JAK2-specific inhibition since this may impact cell signaling of erythropoietin, thrombopoietin, GM-CSF, numerous interleukins and IFNγ, which all signal through JAK2. Negative adverse effects of oral INCB18424 administration have led to limited enthusiasm for this approach. However, topical application of INCB18424 has been shown to bypass adverse effects and results are promising [68]. Phase II trials are underway for both CP-690 550 and INCB18424.

5.2. PDE4 blockers 

Phosphodiesterase 4 (PDE4) cleaves cAMP to decrease concentrations in a variety of inflammatory cells including mast cells, eosinophils, neutrophils, macrophages, T cells, B cells and monocytes, which allows increased downstream effects and cytokine release [70], [71]. AN2728 is an oral PDE4 inhibitor that has been shown to suppress the release of TNFα, IL12, IL23 and other cytokines [72]. Selective PDE4 inhibitors are currently under evaluation for the treatment of asthma and/or chronic obstructive pulmonary disease. Due to the broad anti-inflammatory/immuno-modulatory action of PDE4 inhibitors, it has been proposed that PDE4 inhibitors might also be efficacious for skin disorders such as psoriasis. Both Th1 and Th2 cytokines have been shown to be suppressed by PDE4 inhibitors, suggesting possible utility in psoriasis [73]. Nausea is the most significant side effect of AN2728. Topical application of this compound bypasses this side effect and is currently in phase II trials.

5.3. S1P1 receptor activators 

Sphingosine-1-phosphate (S1P) is a lysophospholipid which is involved in many biological processes. S1P acts through five specific G-protein coupled receptors. Selective agonists of the sphingosine-1-phosphate-1 (S1P1) receptor such as ACT-128800 are of current therapeutic interest for their ability to halt the exit of T-lymphocytes from the thymus, lymph nodes, and other secondary lymphoid organs. This causes interruption of lymphocyte migration and recruitment to inflammatory sites by sequestering the lymphocytes to lymphoid organs. Receptor internalization and negative regulation of T-cell proliferation also result. Furthermore, S1P1 agonists do not affect the innate immune system, such as neutrophils or macrophages, or lymphocyte reactivity to antigen challenge. Therefore, this approach to immunomodulation shows much promise for a variety of autoimmune diseases, including psoriasis [74]. ACT-128800 phase II clinical trials are currently being performed.

Back to Article Outline

6. Conclusion 

Many chemokines and chemokine receptors are potentially involved in the development and maintenance of psoriasis. The redundancy of the chemokine system as a whole involves targeting only one chemokine or chemokine receptor challenging as a concept, but in mouse models inhibiting the CCR6 pathway has demonstrated benefits in models of psoriasis and rheumatoid arthritis. CCR6 and CCL20 have been demonstrated to play important roles in the pathogenesis of IL23-mediated psoriasiform dermatitis in mice. CCL20 is the only CCR6-triggering chemokine and is not able to elicit a biological response through other known chemokine receptors. Both CCL20 and hBD2 are able to recruit CCR6-expressing cells into inflamed epidermis from dermis. Given the possibility that these two peptides redundantly recruit inflammatory cells via CCR6, targeting CCR6 itself with a monoclonal antibody or small molecule would seen to be a better therapeutic strategy compared to targeting CCL20 or hBD2.

Back to Article Outline

Acknowledgment 

This work was supported by a Discovery Grant from the National Psoriasis Foundation to TM and STH.

Back to Article Outline

References 

  1. Christophers E. Psoriasis – epidemiology and clinical spectrum. Clin Exp Dermatol. 2001;26:314–320
  2. Kawada A, Tezuka T, Nakamizo Y, Kimura H, Nakagawa H, Ohkido M, et al. A survey of psoriasis patients in Japan from 1982 to 2001. J Dermatol Sci. 2003;31:59–64
  3. Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med. 1979;301:555
  4. Griffiths CE, Powles AV, Leonard JN, Fry L, Baker BS, Valdimarsson H. Clearance of psoriasis with low dose cyclosporin. Br Med J (Clin Res Ed). 1986;293:731–732
  5. Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK, et al. The vast majority of CLA+ T cells are resident in normal skin. J Immunol. 2006;176:4431–4439
  6. Suarez-Farinas M, Fuentes-Duculan J, Lowes MA, Krueger JG. Resolved psoriasis lesions retain expression of a subset of disease-related genes. J Invest Dermatol. 2011;131:391–400
  7. Homey B, Alenius H, Muller A, Soto H, Bowman EP, Yuan W, et al. CCL27–CCR10 interactions regulate T cell-mediated skin inflammation. Nat Med. 2002;8:157–165
  8. Lonsdorf AS, Hwang ST, Enk AH. Chemokine receptors in T-cell-mediated diseases of the skin. J Invest Dermatol. 2009;129:2552–2566
  9. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med. 2006;354:610–621
  10. Bromley SK, Mempel TR, Luster AD. Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat Immunol. 2008;9:970–980
  11. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627–644
  12. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410:37–40
  13. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–1132
  14. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–1141
  15. Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med. 2009;361:888–898
  16. Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007;9:461–467
  17. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13:715–725
  18. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665–1674
  19. Johnson-Huang LM, Suarez-Farinas M, Sullivan-Whalen M, Gilleaudeau P, Krueger JG, Lowes MA. Effective narrow-band UVB radiation therapy suppresses the IL-23/IL-17 axis in normalized psoriasis plaques. J Invest Dermatol. 2010;130:2654–2663
  20. Genovese MC, Van den Bosch F, Roberson SA, Bojin S, Biagini IM, Ryan P, et al. LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum. 2010;62:929–939
  21. Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2:52ra72
  22. Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med. 2006;203:2577–2587
  23. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445:648–651
  24. Hedrick MN, Lonsdorf AS, Shirakawa AK, Lee CR, Liao F, Singh SP, et al. CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest. 2009;119:2317–2329
  25. Lim HW, Lee J, Hillsamer P, Kim CH. Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells. J Immunol. 2008;180:122–129
  26. Liao F, Alderson R, Su J, Ullrich SJ, Kreider BL, Farber JM. STRL22 is a receptor for the CC chemokine MIP-3a. Biochem Biophys Res Commun. 1997;236:212–217
  27. Greaves DR, Wang W, Dairaghi DJ, Dieu MC, de Saint-Vis B, Franz-Bacon K, et al. CCR6, a CC chemokine receptor that interacts with macrophage inflammatory protein 3a and is highly expressed human dendritic cells. J Exp Med. 1997;186:837–844
  28. Power CA, Church DJ, Meyer A, Alouani S, Proudfoot AE, Clark-Lewis I, et al. Cloning and characterization of a specific receptor for the novel CC chemokine MIP-3α from lung dendritic cells. J Exp Med. 1997;186:825–835
  29. Homey B, Dieu-Nosjean M, Wiesenborn A, Massacrier C, Pin J, Oldham E, et al. Up-regulation of macrophage inflammatory protein-3a/CCL20 and CC chemokine receptor 6 in psoriasis. J Immunol. 2000;164:6621–6632
  30. Fitzhugh DJ, Naik S, Caughman SW, Hwang ST. Cutting edge: CC chemokine receptor-6 (CCR6) is essential for arrest of a subset of memory T cells on activated dermal microvascular endothelial cells under physiologic flow conditions in vitro. J Immunol. 2000;165:6677–6681
  31. Nograles KE, Davidovici B, Krueger JG. New insights in the immunologic basis of psoriasis. Semin Cutan Med Surg. 2010;29:3–9
  32. Hedrick MN, Lonsdorf AS, Hwang ST, Farber JM. CCR6 as a possible therapeutic target in psoriasis. Expert Opin Ther Targets. 2010;14:911–922
  33. Schutyser E, Struyf S, Van Damme J. The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 2003;14:409–426
  34. Yang D, Chertox O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, et al. β-Defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science. 1999;286:525–528
  35. Grinlinton FM, Skinner MA, Birchall NM, Tan PL. γδ+ T cells from patients with psoriatic and rheumatoid arthritis respond to streptococcal antigen. J Rheumatol. 1993;20:982–987
  36. de Boer OJ, Verhagen CE, Visser A, Bos JD, Das PK. Cellular interactions and adhesion molecules in psoriatic skin. Acta Derm Venereol Suppl (Stockh). 1994;186:15–18
  37. Seung NR, Park EJ, Kim CW, Kim KH, Kim KJ, Cho HJ, et al. Comparison of expression of heat-shock protein 60, Toll-like receptors 2 and 4, and T-cell receptor γδ in plaque and guttate psoriasis. J Cutan Pathol. 2007;34:903–911
  38. Laggner U, Di Meglio P, Perera GK, Hundhausen C, Lacy KE, Ali N, et al. Identification of a novel proinflammatory human skin-homing Vγ9Vδ2T cell subset with a potential role in psoriasis. J Immunol. 2011;187:2783–2793
  39. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31:331–341
  40. Gray EE, Suzuki K, Cyster JG. Cutting edge: identification of a motile IL-17-producing γδ T cell population in the dermis. J Immunol. 2011;186:6091–6095
  41. Girardi M, Lewis J, Glusac E, Filler RB, Geng L, Hayday AC, et al. Resident skin-specific γδ T cells provide local, nonredundant regulation of cutaneous inflammation. J Exp Med. 2002;195:855–867
  42. Girardi M. Immunosurveillance and immunoregulation by γδ T cells. J Invest Dermatol. 2006;126:25–31
  43. Mabuchi T, Takekoshi T, Hwang ST. Epidermal CCR6+ γδ T cells are major producers of IL-22 and IL-17 in a murine model of psoriasiform dermatitis. J Immunol. 2011;187:5026–5031
  44. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009;9:679–691
  45. Dieu-Nosjean MC, Massacrier C, Vanbervliet B, Fridman WH, Caux C. IL-10 induces CCR6 expression during Langerhans cell development while IL-4 and IFN-γ suppress it. J Immunol. 2001;167:5594–5602
  46. Dieu-Nosjean MC, Massacrier C, Homey B, Vanbervliet B, Pin JJ, Vicari A, et al. Macrophage inflammatory protein 3α is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J Exp Med. 2000;192:705–718
  47. Komine M, Karakawa M, Takekoshi T, Sakurai N, Minatani Y, Mitsui H, et al. Early inflammatory changes in the “perilesional skin” of psoriatic plaques: is there interaction between dendritic cells and keratinocytes?. J Invest Dermatol. 2007;127:1915–1922
  48. Lowes MA, Chamian F, Abello MV, Fuentes-Duculan J, Lin SL, Nussbaum R, et al. Increase in TNF-α and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc Natl Acad Sci U S A. 2005;102:19057–19062
  49. Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199:125–130
  50. Wang F, Lee E, Lowes MA, Haider AS, Fuentes-Duculan J, Abello MV, et al. Prominent production of IL-20 by CD68+/CD11c+ myeloid-derived cells in psoriasis: gene regulation and cellular effects. J Invest Dermatol. 2006;126:1590–1599
  51. Vestergaard C, Just H, Baumgartner Nielsen J, Thestrup-Pedersen K, Deleuran M. Expression of CCR2 on monocytes and macrophages in chronically inflamed skin in atopic dermatitis and psoriasis. Acta Derm Venereol. 2004;84:353–358
  52. de Groot M, Teunissen MB, Ortonne JP, Lambert JR, Naeyaert JM, Picavet DI, et al. Expression of the chemokine receptor CCR5 in psoriasis and results of a randomized placebo controlled trial with a CCR5 inhibitor. Arch Dermatol Res. 2007;299:305–313
  53. Goebeler M, Toksoy A, Spandau U, Engelhardt E, Brocker EB, Gillitzer R. The C-X-C chemokine Mig is highly expressed in the papillae of psoriatic lesions. J Pathol. 1998;184:89–95
  54. Rottman JB, Smith TL, Ganley KG, Kikuchi T, Krueger JG. Potential role of the chemokine receptors CXCR3, CCR4, and the integrin αEβ7 in the pathogenesis of psoriasis vulgaris. Lab Invest. 2001;81:335–347
  55. Wen H, Hogaboam CM, Lukacs NW, Cook DN, Lira SA, Kunkel SL. The chemokine receptor CCR6 is an important component of the innate immune response. Eur J Immunol. 2007;37:2487–2498
  56. Jansen PA, Rodijk-Olthuis D, Hollox EJ, Kamsteeg M, Tjabringa GS, de Jongh GJ, et al. β-Defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin. PLoS One. 2009;4:e4725
  57. Hollox EJ, Huffmeier U, Zeeuwen PL, Palla R, Lascorz J, Rodijk-Olthuis D, et al. Psoriasis is associated with increased β-defensin genomic copy number. Nat Genet. 2008;40:23–25
  58. Chen SC, de Groot M, Kinsley D, Laverty M, McClanahan T, Arreaza M, et al. Expression of chemokine receptor CXCR3 by lymphocytes and plasmacytoid dendritic cells in human psoriatic lesions. Arch Dermatol Res. 2010;302:113–123
  59. Homey B, Meller S. Chemokines and other mediators as therapeutic targets in psoriasis vulgaris. Clin Dermatol. 2008;26:539–545
  60. Wells TN, Power CA, Shaw JP, Proudfoot AE. Chemokine blockers – therapeutics in the making?. Trends Pharmacol Sci. 2006;27:41–47
  61. Schroder JM, Christophers E. Identification of C5adesarg and an anionic neutrophil-activating peptide (ANAP) in psoriatic scales. J Invest Dermatol. 1986;87:53–58
  62. Fukuoka M, Ogino Y, Sato H, Ohta T, Komoriya K, Nishioka K, et al. RANTES expression in psoriatic skin, and regulation of RANTES and IL-8 production in cultured epidermal keratinocytes by active vitamin D3 (tacalcitol). AAD Rev. 1998;138:63–70
  63. Raychaudhuri SP, Jiang WY, Farber EM, Schall TJ, Ruff MR, Pert CB. Upregulation of RANTES in psoriatic keratinocytes: a possible pathogenic mechanism for psoriasis. Acta Derm Venereol. 1999;79:9–11
  64. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204:2803–2812
  65. Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, Schlessinger A, et al. Ligand discovery from a dopamine D(3) receptor homology model and crystal structure. Nat Chem Biol. 2011;7:769–778
  66. Veldkamp CT, Ziarek JJ, Peterson FC, Chen Y, Volkman BF. Targeting SDF-1/CXCL12 with a ligand that prevents activation of CXCR4 through structure-based drug design. J Am Chem Soc. 2010;132:7242–7243
  67. Yamaoka K, Tanaka Y. Jak inhibitor; possibility and mechanism as a new disease modifying anti-rheumatic drug. Nihon Rinsho Meneki Gakkai Kaishi. 2009;32:85–91
  68. Cohen S, Fleischmann R. Kinase inhibitors: a new approach to rheumatoid arthritis treatment. Curr Opin Rheumatol. 2010;22:330–335
  69. Kawamura M, McVicar DW, Johnston JA, Blake TB, Chen YQ, Lal BK, et al. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci U S A. 1994;91:6374–6378
  70. Harada D, Takada C, Nosaka Y, Takashima Y, Kobayashi K, Takaba K, et al. Effect of orally administered KF66490, a phosphodiesterase 4 inhibitor, on dermatitis in mouse models. Int Immunopharmacol. 2009;9:55–62
  71. Spina D. PDE4 inhibitors: current status. Br J Pharmacol. 2008;155:308–315
  72. Nazarian R, Weinberg JM. AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs. 2009;10:1236–1242
  73. Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6:17–26
  74. Bolli MH, Abele S, Binkert C, Bravo R, Buchmann S, Bur D, et al. 2-Imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J Med Chem. 2010;53:4198–4211
  75. Giustizieri ML, Mascia F, Frezzolini A, De Pita O, Chinni LM, Giannetti A, et al. Keratinocytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T cell-derived cytokines. J Allergy Clin Immun. 2001;107:871–877
  76. Uchida T, Suto H, Ra C, Ogawa H, Kobata K, Okumura K. Preferential expression of T(h)2-type chemokine and its receptor in atopic dermatitis. Int Immunol. 2002;14:1431–1438
  77. Teraki Y, Miyake A, Takebayashi R, Shiohara T. Homing receptor and chemokine receptor on intraepidermal T cells in psoriasis vulgaris. Clin Exp Dermatol. 2004;29:658–663
  78. Morita E, Kameyoshi Y, Hiragun T, Mihara S, Yamamoto S. The C-C chemokines, RANTES and eotaxin, in atopic dermatitis. Allergy. 2001;56:194–195
  79. Kakinuma T, Saeki H, Tsunemi Y, Fujita H, Asano N, Mitsui H, et al. Increased serum cutaneous T cell-attracting chemokine (CCL27) levels in patients with atopic dermatitis and psoriasis vulgaris. J Allergy Clin Immunol. 2003;111:592–597
  80. Campanati A, Goteri G, Simonetti O, Ganzetti G, Giuliodori K, Stramazzotti D, et al. CTACK/CCL27 expression in psoriatic skin and its modification after administration of etanercept. Br J Dermatol. 2007;157:1155–1160
  81. Schulz BS, Michel G, Wagner S, Suss R, Beetz A, Peter RU, et al. Increased expression of epidermal IL-8 receptor in psoriasis. Down-regulation by FK-506 in vitro. J Immunol. 1993;151:4399–4406
  82. Kulke R, Bornscheuer E, Schluter C, Bartels J, Rowert J, Sticherling M, et al. The CXC receptor 2 is overexpressed in psoriatic epidermis. J Invest Dermatol. 1998;110:90–94
  83. Gillitzer R, Ritter U, Spandau U, Goebeler M, Brocker EB. Differential expression of GRO-α and IL-8 mRNA in psoriasis: a model for neutrophil migration and accumulation in vivo. J Invest Dermatol. 1996;107:778–782
  84. Yamashita T, Akamatsu H, Tomitaka A, Ogawa Y, Sugawara N, Matsunaga K. IP-10 in atopic dermatitis. Allergy. 2003;58:261
  85. Oh ST, Schramme A, Tilgen W, Gutwein P, Reichrath J. Overexpression of CXCL16 in lesional psoriatic skin. Dermatoendocrinology. 2009;1:114–118
  86. Fraticelli P, Sironi M, Bianchi G, D’Ambrosio D, Albanesi C, Stoppacciaro A, et al. Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses. J Clin Invest. 2001;107:1173–1181
biography

Tomotaka Mabuchi, is an assistant professor in Department of Dermatology, Tokai University School of Medicine, Kanagawa, Japan (Chief: Prof. Akira Ozawa). He graduated from Tokai University school of Medicine in 1999. He has performed research on the genetics of psoriasis in the Department of Molecular Life Science, Tokai University School of Medicine (Chief: Prof. Hidetoshi Inoko) and received his Ph.D. degree from Tokai University in 2007. He was secretary general of the 24th Annual Meeting of the Japanese Society for Psoriasis Research in 2009. Since 2009, he has conducted research on the immunology of psoriasis in the Department of Dermatology, Medical College of Wisconsin, WI, USA (PI: Prof. Sam T. Hwang).

PII: S0923-1811(11)00323-9

doi:10.1016/j.jdermsci.2011.11.007

Journal of Dermatological Science
Volume 65, Issue 1 , Pages 4-11, January 2012

Article Tools

* Image Usage & Resolution