K16 expression in uninvolved psoriatic skin: a possible marker of pre-clinical psoriasis

BACKGROUND: K16, a type I keratin, is upregulated in hyperproliferative states including psoriasis. It has been used as a marker of psoriasis and its expression is upregulated in relapsing psoriasis and downregulating in resolving. We evaluated non-lesional psoriatic skin for K16 expression. METHODS: Sixty-seven non-lesional and lesional skin samples from patients with psoriasis and normal skin from 19 non-psoriatic patients were studied by immunohistochemistry on frozen sections with K16. RESULTS: Seventeen of 19 normal skin samples showed staining of basal cells in the deeper part of the rete ridges. Sixty-two non-lesional psoriatic skin samples showed intense basal staining of K16. Of the remaining five non-lesional samples, diffuse intense suprabasal staining in one, pan-epidermal staining in two, and no staining was seen in two samples. Suprabasal (37), diffuse (14), sandwich (12), and basal (3) pattern staining were seen in psoriatic skin. One psoriatic skin sample did not show any expression. CONCLUSION: Our results demonstrate that K16 expression is also observed in non-lesional psoriatic skin and may serve as a marker of preclinical psoriasis.     

Mesenchymal stem cells in psoriatic lesions affect the skin microenvironment through circular RNA

Psoriasis is an autoimmune skin disease. Our previous studies revealed abnormal immune regulation of skin mesenchymal stem cells (S‐MSCs) in psoriatic lesions. Circular RNA (circRNA) molecules were recently discovered as a new class of non‐coding regulatory RNAs. Their role in the pathogenesis of psoriasis has not yet been studied. To explore potential circRNA‐mediated mechanisms of S‐MSCs in the pathogenesis of psoriasis, we sequenced mRNAs and circRNAs of MSCs from normal skin and psoriatic lesions, followed by functional prediction and interaction analyses. In total, 129 circRNAs were differentially expressed, including 123 up‐regulated and 6 down‐regulated circRNAs, in MSCs from psoriatic lesions. Pathway analysis showed that the genes significantly down‐regulated in psoriatic as compared to normal S‐MSCs were mainly involved in JAK‐STAT signalling. According to a circRNA‐miRNA‐mRNA interaction network, the expression of circRNAs associated with these mRNAs was also down‐regulated in MSCs of psoriatic skin lesions. Knockdown of the circRNA gene chr2:206992521|206994966 reduced the capacity of S‐MSCs to inhibit T‐cell proliferation upon co‐culture in normal as well as lesion‐derived S‐MSCs. Secreted‐cytokine profiles (IL‐6, IL‐11 and hepatocyte growth factor) were also similar in normal and lesion‐derived S‐MSCs after circRNA knockdown. Thus, the circRNA chr2:206992521|206994966 in S‐MSCs from psoriatic lesions affects the activity of T lymphocytes in local lesions by influencing their cytokine secretion. Taken together, our findings indicate that circRNA mediates the role of S‐MSCs in the pathogenesis of psoriasis.     

Abnormal maturation pathway of keratinocytes in psoriatic skin

We compared the maturation pathway of normal and psoriatic epidermis using three different markers: (1) Involucrin, which is normally detected in the stratum granulosum in normal skin, was detected in all but the basal layer of involved psoriatic skin; (2) an antigen, recognized by the murine monoclonal antibody psi 3, was present in all but the basal layer of involved psoriatic skin but was absent from uninvolved and normal skin; (3) fibronectin, which normally localizes in the dermis and the epidermal-dermal junction, was also detected intra- and extracellularly in the psoriatic epidermis. These results indicate that the alterations in keratinocyte maturation found in psoriasis do not arise from a truncation of the normal maturation pathway but rather reflect the onset of an abnormal pathway of differentiation characterized by the expression of psi 3 antigen and fibronectin and the premature appearance of involucrin.     

Epidermal growth in the skin equivalent

Summary The skin equivalent (SE) has been validated as a model for studies on proliferation of keratinocytes. SEs were prepared from normal skin by implanting punch biopsies on dermal equivalents consisting of fibroblasts in a collagen matrix. The outgrowths were measured by planimetry. An immunohistochemical investigation with antibodies against markers associated with proliferation was performed on frozen sections from SEs during outgrowth at 3–6 days (SE6) as well as after completion of outgrowth at 21 days (SE21). Biopsies from normal controls and from uninvolved and involved skin in psoriatic patients were also studied. The antibodies used were Ki-67, cytokeratin 8.12, and antibodies against the receptors for epidermal growth factor (EGFr) and transferrin (TFr). The increase in area was linear during the first 7 days of culture and usually reached the edges of the dermal equivalent at this time. In SE6 TFr was expressed in the basal part of the outgrowth while the other markers were not observed. In SE21 and in psoriasis there was abundant epidermal staining of Ki-67-positive nuclei and cytokeratin 8.12 was detected in the suprabasal part of the epidermis. EGFr and TFr were seen in the basal layer in SE21. In the psoriatic lesions these receptors were found both in the basal and suprabasal layers. The lack of proliferation markers in SE6 indicates that the initial increase in the area of keratinocytes is due to migration from the punch biopsies. Increased cell proliferation is present in SE21, a finding in common with psoriasis and wound healing. The skin equivalents should therefore be an appropriate model for studies on these phenomena.     

Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis

BACKGROUND: Toll-like receptors (TLRs) are part of the innate immune system involved in the response to microbial pathogens. TLR2 recognizes various ligands expressed by Gram-positive bacteria, while TLR3, TLR4 and TLR5 are specific for double-stranded RNA, Gram-negative lipopolysaccharides and bacterial flagellin, respectively. OBJECTIVES: To determine, firstly, whether epidermal keratinocytes of normal skin express TLRs and, secondly, whether modulation of TLR expression occurs in psoriasis, an inflammatory skin disease associated with certain microorganisms such as streptococci, staphylococci and yeasts. METHODS: Eight samples of normal, and 15 samples of lesional and nonlesional psoriatic skin were stained with polyclonal antibodies specific for TLR1-5 using an avidin-biotin-peroxidase technique. RESULTS: Epidermal keratinocytes in normal skin constitutively expressed TLR1, TLR2 and TLR5, while TLR3 and TLR4 were, in most cases, barely detectable. Cytoplasmic TLR1 and TLR2 were expressed throughout the epidermis, with higher staining of the latter on basal keratinocytes, while TLR5 expression was concentrated in the basal layer. In contrast, in lesional epidermis from patients with psoriasis, TLR2 was more highly expressed on the keratinocytes of the upper epidermis than on the basal layer, while TLR5 was downregulated in basal keratinocytes compared with corresponding nonlesional psoriatic epidermis. In addition, nuclear TLR1 staining was observed in the upper layers of both nonlesional and lesional psoriatic epidermis, but not in that of normal skin. CONCLUSIONS: These findings suggest that TLRs expressed by epidermal keratinocytes constitute part of the innate immune system of the skin. The relevance of altered keratinocyte TLR expression in psoriasis remains to be determined.     

Histochemical localization of hyaluronan in psoriasis, allergic contact dermatitis and normal skin.

In suction blister fluid from active psoriatic lesions we have previously found elevated concentrations of hyaluronan. The aim of this investigation was to study the localization of hyaluronan with a histochemical method, in biopsy specimens from lesions of 13 patients with progressive psoriasis. Ten normal subjects and seven patients with allergic contact dermatitis were also studied. In normal epidermis the highest intensity of hyaluronan staining was found in the intercellular spaces in the middle and upper spinous layer, whereas the staining was much weaker in the basal layer. No hyaluronan was detected in the granular layer or in the orthokeratotic stratum corneum. In the dermis there was pronounced staining of the papillary dermis and around the sebaceous glands, sweat glands, hair follicles and blood vessels. In six of the 16 specimens from psoriatic lesions the normal epidermal meshwork of hyaluronan was partly absent and replaced by diffuse staining of both the spinous and the basal layer. In the remaining ten of these 16 specimens the same type of meshwork was found in stratum spinosum as in normal skin. The parakeratotic stratum corneum contained hyaluronan, in contrast to the normal stratum corneum, where no hyaluronan was present. The pattern of hyaluronan staining in the dermis of the psoriatic lesions did not differ from that in normal dermis. In the majority of the allergic patch test reactions the junction was less distinct than in normal skin between dermis and epidermis and the normal hyaluronan pattern of the basal layer was abolished and replaced by a diffuse staining throughout the layer.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered cutaneous innervation in psoriatic skin as revealed by PGP 9.5 immunohistochemistry

Summary There is conflicting evidence in the literature as to whether cutaneous nerves are altered in psoriasis or not. In this study, antibodies to protein gene product (PGP) 9.5 were used to visualize cutaneous nerves in biopsies from involved and uninvolved skin of nine patients with psoriasis and from normal skin of eight healthy controls. A profound reduction in the epidermal nerve fibre density was observed in the involved psoriatic skin. These intraepidermal nerve fibres were also mostly short and found in the basal layer. Only a few nerve fibres were found in the suprabasal layer and they were non-varicose, long fibres going straight up without branching. In the uninvolved skin of psoriatic patients, the distribution and number of the intraepidermal nerve fibres was similar to that observed in normal skin. In the dermis, the distribution and the number of the nerve fibres showed no differences between involved psoriatic skin, uninvolved psoriatic skin, and normal skin. The results support previous studies in which alterations of cutaneous nerves in psoriasis have been described.     

CD26/dipeptidyl-peptidase IV in psoriatic skin: upregulation and topographical changes

Background Psoriasis is known to affect 2–3% of the population and can be considered an organ‐specific autoimmune disease. CD26/dipeptidyl‐peptidase IV (DPP‐IV) is a membrane‐bound protease with diverse properties. In theory, the expression of CD26/DPP‐IV has common grounds with three principal key players of the psoriatic pathogenesis: keratinocytes, T cells and cytokines. Objectives To assess CD26/DPP‐IV expression in psoriasis in order to expand on the search for complementary biomarkers related to inflammation and proliferation in psoriasis. Methods The pattern of expression of CD26/DPP‐IV was investigated on the mRNA‐, protein‐ and enzyme‐functionality level using immunohistochemical, immunofluorescent and enzyme activity labelling techniques. Results An 11‐fold significant increase of CD26/DPP‐IV on the mRNA level was demonstrated in psoriatic epidermal sheets compared with normal skin. Immunohistochemistry on psoriatic sections showed a distinct patchy honeycomb‐like CD26/DPP‐IV staining in the suprapapillary layers. Moreover, a clearly distinguishable column‐like staining pattern throughout the suprabasal compartment along the rete ridges was seen, whereas in normal skin these patterns were absent. Strikingly, CD26/DPP‐IV enzyme activity correlated with this immunohistochemical reactivity pattern for the CD26/DPP‐IV protein. The T‐cell bound expression of CD26/DPP‐IV in psoriatic skin was explicitly present, albeit in small quantities. Conclusions Our data provide clear evidence for a versatile upregulation of CD26/DPP‐IV expression in psoriatic (epi)dermis. Although the exact functional contribution remains speculative, the topographical distribution of this complex multifunctional protein suggests a suitable role as a complementary biomarker in psoriasis.     

Laser capture microdissection followed by next‐generation sequencing identifies disease‐related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis

Psoriasis is a systemic disease with cutaneous manifestations. MicroRNAs (miRNAs) are small non‐coding RNA molecules that are differentially expressed in psoriatic skin; however, only few cell‐ and region‐specific miRNAs have been identified in psoriatic lesions. We used laser capture microdissection (LCM) and next‐generation sequencing (NGS) to study the specific miRNA expression profiles in the epidermis (Epi) and dermal inflammatory infiltrates (RD) of psoriatic skin (N = 6). We identified 24 deregulated miRNAs in the Epi and 37 deregulated miRNAs in the RD of psoriatic plaque compared with normal psoriatic skin (FCH > 2, FDR < 0.05). Interestingly, 9 of the 37 miRNAs in RD, including miR‐193b and miR‐223, were recently described as deregulated in circulating peripheral blood mononuclear cells (PBMCs) from patients with psoriasis. Using flow cytometry and qRT‐PCR, we found that miR‐193b and miR‐223 were expressed in Th17 cells. In conclusion, we demonstrate that LCM combined with NGS provides a robust approach to explore the global miRNA expression in the epidermal and dermal compartments of psoriatic skin. Furthermore, our results indicate that the altered local miRNA changes seen in the RD are reflected in the circulating immune cells, suggesting that miRNAs may contribute to the pathogenesis of psoriasis.     

Genital psoriasis: a questionnaire‐based survey on a concealed skin disease in the Netherlands

Background Psoriatic lesions may involve nearly all sites of the body. Involvement of the genital skin is frequently classified as part of intertriginous psoriasis without special awareness and treatment for this presentation of the disease. Gaining knowledge about the frequency of the involvement of genital skin in these patients will improve the overall care for patients with psoriasis. Objectives We studied the prevalence of genital psoriasis in the Netherlands and epidemiological characteristics of this specific presentation of the disease. Furthermore, we studied the relation between flexural and genital psoriasis. Patients/Methods A self‐administered questionnaire was sent to all 5300 members of the Dutch Psoriasis Society. Sociodemographic patient characteristics and disease‐related data (such as localization of psoriatic lesions, involvement of the genitalia, age at onset of genital psoriasis and severity of genital psoriatic lesions) were collected and analysed. Results A response rate of 37% was achieved. Almost 46% of the responding patients with psoriasis, that is 16.5% of all potential responders (n = 5300), report genital involvement at some time during the course of their disease. The genitalia can become affected at any age. Many patients with current genital involvement (38%) do not have the flexural skin affected. Conclusions A large part of patients with psoriasis suffer from genital psoriasis, which was not associated with flexural involvement in at least one third of them. More attention to the genital region is required in the current standard treatment of both male and female psoriatic patients at any age.     

Reciprocal altered expression of T-cadherin and P-cadherin in psoriasis vulgaris

BACKGROUND: The most characteristic change in psoriasis vulgaris is markedly increased, persistent keratinocyte proliferation. The underlying mechanism of excessive epidermal growth is controversial. We previously found and reported that T-cadherin was expressed in keratinocytes and confined to the basal layer of mouse and human skin. Invasive cutaneous squamous cell carcinoma showed a loss of T-cadherin expression. Another study showed that T-cadherin was a negative growth regulator of epidermal growth factor in T-cadherin transfectant neuroblastoma cells. OBJECTIVES: To obtain insight into the role of T-cadherin in keratinocyte proliferation and to investigate further the pathogenesis of psoriasis vulgaris, we examined the expression of T-cadherin, as well as E- and P-cadherin, in psoriasis vulgaris. METHODS: Four untreated active psoriatic skin samples from psoriasis vulgaris patients and four normal human skin samples from plastic surgery were collected, cryosectioned and immunohistochemically stained by antihuman T-, P- and E-cadherin antibodies. Further, the immunofluorescence intensities of T- and P-cadherin on the basal layer of the epidermis were quantitatively measured by the histogram function of LSM 510 software installed in a Zeiss laser scanning confocal microscope. The data were statistically analysed by Student's t-test. RESULTS: It was observed that T-cadherin was weakly and discontinuously expressed on the basal layer of psoriatic skin, while it was intensively expressed on all basal keratinocytes in normal human skin. In contrast, P-cadherin was strongly expressed throughout the entire epidermal layer in psoriatic skin samples, although its expression is restricted to the basal cell layer in normal human skin. There were no obvious differences in E-cadherin expression between normal human skin and psoriatic skin. Statistical analyses showed that the immunofluorescence intensity of T-cadherin in the basal cell layer of psoriatic skin (35 +/- 9.08) was significantly decreased compared with that in normal human skin (131.75 +/- 3.49, P = 2.46 x 10(-6)). There was a significant increase (P = 0.00139) in the immunofluorescence intensity of P-cadherin in the basal layer of psoriatic skin (68.25 +/- 12.13) compared with normal human skin (26 +/- 4.90). CONCLUSIONS: The present study demonstrates that there is downregulation of T-cadherin expression and upregulation of P-cadherin expression in psoriatic skin, which are considered to be involved in the hyperproliferation of keratinocytes in psoriasis vulgaris.     

Prolactin level is significantly elevated in lesional skin of patients with psoriasis

Background Accumulating data point to a potential role of prolactin in the pathogenesis of psoriasis. Methods We initiated a study including psoriasis patients (n = 15) and healthy volunteers (n = 15) as controls. Psoriasis area and severity index (PASI) score was evaluated, and prolactin levels in serum and blister fluid were assessed by enzyme‐linked immunosorbent assay (ELISA). Results Prolactin levels were significantly (P < 0.01) elevated in blister fluid of psoriatic lesional skin. Correlations between PASI score and different serum prolactin levels in lesional and non‐lesional skin were insignificant. Significant positive correlations of prolactin level were observed between lesional and non‐lesional skin in psoriasis (P < 0.05) and between serum and clinically normal skin in both psoriasis and control subjects (P < 0.05). Conclusions Locally produced prolactin may be involved in the pathogenesis of psoriatic lesions.     

Differentiation-associated localization of small prolne-rich rotein in normal and diseased human skin

Summary The expression of SPRR (small proline-rich protein) was investigated in normal human skin and in diseased skin from patients with psoriasis, squamous cell carcinoma, basal cell epithelioma. Naevus pigmentosus, ichthyosis vulgaris and several inflammatory skin diseases, by immunohistochemical staining. A polyclonal antibody was raised against a synthetic peptide for a C-terminal common region for SPRR l and SPRR 3. In immunoblot analysis, a positive band of 18kDa was detected, which showed the presence of SPRR l in human epidermal keratinocytes. In normal epidermis, positive staining for SPRK was observed in keratinocytes in the granular layer and the uppermost or two spinous cell layers, with no staining of the other spinous or basal layers. The staining was obvious at the cell periphery, weak at the cytoplasm, and absent in the nucleus. Staining was observed in several outer layers of the follicular infundibulum to the isthmus. No staining was detected in the inner root sheath of the hair follicles, hair matrix, sebaceous gland, eccrine gland, eccrine duct, melanocytes. Langerhans cells or fibroblasts. The arrectores pilorum, striated muscles, muscle layers of vessels, and myoepithelia of eccrine gland, were weakly stained. In psoriatic skin, stained keratinocytes were distributed in the spinous cell layers except for the basal layer, in ichthyosis vulgaris. SPRR was barely expressed in the uppermost living cell layers of the epidermis in epidermolytic hyperkeratosis. degenerated squamous cells widely expressed SPRR. In Darier's disease, dyskeratolic cells were clearly stained. In squamous cell carcinoma, staining was observed in keratotic cells around horny pearls. In basal cell epithelioma, naevus pigmentosus, and malignant melanoma, the tumour cells or naevus cells were not stained. The distribution of SPRR was similar to that of involucrin in normal and several diseased skin, except for ichthyosis vulgaris. We conclude that SPRR is expressed in close association with epidermal differentiation in normal skin and skin diseases. The alteration of the expression of the proteins correlated to terminal differentiation, and differs from disease to disease.     

Fas Bax和bcl-2蛋白在银屑病病人表皮细胞中的表达

目的观察银屑病病人表皮细胞凋亡中凋亡基因Ｆａｓ、Ｂａｘ（ｂ ｃｅｌ相关基因）和凋亡抑制基因ｂｃｌ ２（Ｂ ｃｅｌＬｙｍｐｈｏｍａ／Ｌｅｕｋｅｍｉａ２）的作用及其相互关系。方法采用免疫组化染色法在３３例银屑病皮损标本中,观察了Ｆａｓ、Ｂａｘ及ｂｃｌ ２蛋白的表达。结果发现３３例银屑病皮损标本中,Ｆａｓ２９例阳性表达;Ｂａｘ２３例阳生;３３例ｂｃｌ ２表达皆阴性。５例正常对照中,Ｆａｓ及Ｂａｘ皆阴性,ｂｃｌ ２在基底层细胞中阳性。结论结果提示Ｆａｓ和Ｂａｘ蛋白的高表达、ｂｃｌ ２的不表达与银屑病损害中表皮细胞凋亡增多有关。     

Expression of serotonergic receptors in psoriatic skin

Psoriasis appears to be influenced by stress, which causes release of adrenal hormones. Serotonin, or hormonal actions on serotonin and serotonin receptors, may have a role in psoriasis. Distribution of serotonin receptors was studied in involved and noninvolved skin in patients with psoriasis and compared to normal skin, by using immunohistochemistry and antibodies to 5-HT1A, 5-HT2A and 5-HT3 receptors (R). There was a decreased (P<0.001) number of 5-HT1AR positive cells, the majority being tryptase positive, in involved and noninvolved psoriatic papillary dermis, compared to normal skin. 5-HTlAR expression was also found in the upper part of the epidermis, on vessel walls and on melanocytes. 5-HT2AR expressing papillary mononuclear cells, CD3 positive, were increased (P<0.001 and P<0.01, respectively) in involved and noninvolved psoriatic skin, compared to normal skin, an increase (P<0.01) also being found in the involved compared to noninvolved skin. Expression of 5-HT3R could be found in the basal epidermal layer of noninvolved but not in the involved skin of psoriasis, where it was only found in the acrosyringium. The present findings are compatible with the 5-HT1A and 5-HT2A receptors having antagonistic functions, and raise the possibility of using receptor specific drugs in the treatment of psoriasis.     

Alteration of the expression of Bcl-2, Bcl-x,Bax, Fas,and Fas ligand in the involved skin of psoriasis vulgaris following topical anthralin therapy

Anthralin (dithranol) is frequently used for the treatment of psoriasis. However, the mode of action of anthralin has not been completely elucidated as yet. Recent findings suggest that psoriatic keratinocytes are resistant to the apoptotic process. In this study, we examined the immunohistochemical expression of apoptosis-regulated protein in the involved psoriatic skin following topical anthralin therapy. Biopsy specimens were obtained from back skins treated with topical anthralin or white petrolatum (control) in 4 patients with psoriasis vulgaris. Immunohistochemical examination revealed that psoriatic keratinocytes expressed high levels of Bcl-x, which was significantly reduced after anthralin treatment. Bax was not detected in the epidermal keratinocytes in the petrolatum-treated skin, while it was present in the upper keratinocytes after anthralin therapy. Bcl-2 was detected only in basal layers of psoriatic epidermis following both petrolatum and anthralin application. Psoriatic keratinocytes expressed higher levels of Fas in the lower epidermis, while only weak expression was detected in anthralin-treated plaques. On the other hand, hyperproliferative keratinocytes strongly expressed Fas ligand (FasL) on their plasma membranes as well as infiltrating lymphocytes in the upper dermis. Furthermore, anthralin-treated psoriatic epidermis did not express FasL. In normal skin, keratinocytes expressed low to absent levels of Bcl-x and Bax, while Bcl-2 was detected only in melanocytes in basal layers. Neither Fas nor FasL were detected in the epidermis of normal skin. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining revealed positive labeling on the majority of psoriatic keratinocytes through the epidermis in petrolatum-treated skin, whereas anthralin treatment markedly reduced TUNEL-positive keratinocytes. These in vivo results may reflect improvement of the psoriatic skin following effective anthralin therapy.     

The expression of syndecan-1 in psoriatic epidermis

Psoriasis is a chronic inflammatory skin disease characterized by exaggerated keratinocyte proliferation. Current opinion 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 an intrinsic alteration in epidermal keratinocytes plays a very important role in disease expression. Syndecans comprise a major family of cell surface heparan sulfate proteoglycans. Several studies indicate their role in adhesion, cell-extracellular matrix interactions, migration, keratinocyte proliferation and differentiation, inflammation, and wound healing. To determine the expression of syndecan-1 in psoriasis, skin samples from 29 patients with fully developed psoriasis and skin samples from 14 healthy volunteer persons with no personal or family history of psoriasis were immunohistochemically examined using monoclonal antibody against syndecan-1. The expression of syndecan-1 was analyzed in whole mount section of psoriatic and non-psoriatic skin biopsies under high magnification (400x). In addition, the intensity and topography of reaction in the cell, as well as localization of positive cells in the epidermis were evaluated. Strong syndecan-1 reactivity in epidermal cells in all non-psoriatic and psoriatic samples was observed. Statistical analysis showed no significant differences between two analyzed groups (P > 0.05). In normal skin syndecan-1 was expressed in full thickness of the epidermis. The strongest reaction was observed in membranes and intercellular junctions of spinous and granular layer while basal cells showed weaker expression that was confined to cytoplasm. In psoriatic skin syndecan-1 was expressed in the membrane and intercellular junction of cells located in thickened and elongated rete ridges of the epidermis. The strongest reaction was in basal and suprabasal layers and expression diminished through spinous layer. Cells in spinous layer lose syndecan-1 expression, which is opposite pattern to normal skin. Our results suggest that aberrant skin expression of syndecan-1 may be involved in the development of psoriasis.     

CCL7 contributes to the TNF‐alpha‐dependent inflammation of lesional psoriatic skin

Chemokines are small chemotactic proteins that have a crucial role in leukocyte recruitment into tissue. Targeting these mediators has been suggested as a potential therapeutic option in inflammatory skin diseases such as psoriasis. Using quantitative RT‐PCR, we found CCL7, a chemokine ligand known to interact with multiple C‐C chemokine receptors, to be markedly increased in lesional psoriasis as opposed to atopic dermatitis, lichen planus, non‐lesional psoriatic and normal control skin. Surprisingly, this increase in CCL7 mRNA expression exceeded that of all other chemokines investigated, and keratinocytes and dermal blood endothelial cells were identified as its likely cellular sources. In an imiquimod‐induced psoriasis‐like mouse model, CCL7 had a profound impact on myeloid cell inflammation as well as on the upregulation of key pro‐psoriatic cytokines such as CCL20, IL‐12p40 and IL‐17C, while its blockade led to an increase in the antipsoriatic cytokine IL‐4. In humans receiving the TNF‐α‐blocker infliximab, CCL7 was downregulated in lesional psoriatic skin already within 16 hours after a single intravenous infusion. These data suggest that CCL7 acts as a driver of TNF‐α‐dependent Th1/Th17‐mediated inflammation in lesional psoriatic skin.