Development Of Skin Inflammation Research Articles

C-type lectin receptor expression is a hallmark of neutrophils infiltrating the skin in epidermolysis bullosa acquisita.

Inflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA closely mirrors this EBA phenotype. To better understand the changes induced in neutrophils upon recruitment from peripheral blood into lesional skin in EBA, we performed single-cell RNA-sequencing of whole blood and skin dissociate to capture minimally perturbed neutrophils and characterize their transcriptome. Through this approach, we identified clear distinctions between circulating activated neutrophils and intradermal neutrophils. Most strikingly, the gene expression of multiple C-type lectin receptors, which have previously been reported to orchestrate host defense against fungi and select bacteria, were markedly dysregulated. After confirming the upregulation of Clec4n, Clec4d, and Clec4e in experimental EBA as well as in lesional skin from patients with inflammatory EBA, we performed functional studies in globally deficient Clec4e-/- and Clec4d-/- mice as well as in neutrophil-specific Clec4n-/- mice. Deficiency in these genes did not reduce disease in the EBA model. Collectively, our results suggest that while the upregulation of Clec4n, Clec4d, and Clec4e is a hallmark of activated dermal neutrophil populations, their individual contribution to the pathogenesis of EBA is dispensable.

Atopic dermatitis and the human skin microbiota

The skin microbiota is a complex ecosystem consisting of bacteria, fungi and viruses. The role of the human skin microbiota is to maintain homeostasis in the body. Disruption of the balance of the natural composition of the human microbiome can lead to the development of inflammation and infection. Atopic dermatitis is a chronic and recurrent non-infectious, inflammatory dermatosis characterised by erythematous and exfoliative skin lesions, accompanied by pruritus and a tendency to superinfection. Defect in the epidermal barrier, immune dysfunction and changes in the composition of the skin microbiome underlie the pathogenesis of atopic dermatitis. It has been found that the diversity of atopic skin microbiota is significantly reduced, with a decrease in the number of Cutibacterium, Streptococcus, Acinetobacter, Corynebacterium and Prevotella, and a concomitant increase in the percentage of Staphylococcus bacteria, especially S. aureus. It accounts for about 20% of skin microbiome in healthy people, while in patients with atopic dermatitis the percentage of S. aureus can increase up to 30–100%. In addition, there is a positive correlation between S. aureus skin colonisation and disease severity. S. aureus plays a key role in the development of skin inflammation in the course of atopic dermatitis, including through the induction of lymphocyte expansion, release of cytokines, pro-inflammatory lipoproteins, and stimulation of mast cell degranulation. Therefore, properly selected and regular treatment of atopic dermatitis diversifies the skin microflora, often leading to clinical improvement in the patient.

Alpha-Mangostin: A Potent Inhibitor of TRPV3 and Pro-Inflammatory Cytokine Secretion in Keratinocytes.

The TRPV3 calcium ion channel is vital for maintaining skin health and has been associated with various skin-related disorders. Since TRPV3 is involved in the development of skin inflammation, inhibiting TRPV3 could be a potential treatment strategy. Alpha-mangostin isolated from Garcinia mangostana L. extract exhibits diverse positive effects on skin health; however, the underlying mechanisms remain obscure. This study investigated the TRPV3-inhibitory properties of alpha-mangostin on TRPV3 hyperactive mutants associated with Olmsted syndrome and its impact on TRPV3-induced cytokine secretion and cell death. Our findings demonstrate that alpha-mangostin effectively inhibits TRPV3, with an IC50 of 0.077 ± 0.013 μM, showing inhibitory effects on both wild-type and mutant TRPV3. TRPV3 inhibition with alpha-mangostin decreased calcium influx and cytokine release, protecting cells from TRPV3-induced death. These results indicate that alpha-mangostin reduced inflammation in TRPV3-activated skin keratinocytes, suggesting that alpha-mangostin could be potentially used for improving inflammatory skin conditions such as dermatitis.

Mitochondrial Reactive Oxygen Species Are Essential for the Development of Psoriatic Inflammation

Psoriasis is a common immune-mediated, chronic, inflammatory skin disease that affects approximately 2–3% of the population worldwide. Although there is increasing evidence regarding the essential roles of the interleukin (IL)-23/IL-17 axis and dendritic cell (DC)-T cell crosstalk in the development of skin inflammation, the contributions of mitochondrial function to psoriasis are unclear. In a mouse model of imiquimod (IMQ)-induced psoriasiform skin inflammation, we found that hematopoietic cell-specific genetic deletion of p32/C1qbp, a regulator of mitochondrial protein synthesis and metabolism, protects mice from IMQ-induced psoriatic inflammation. Additionally, we demonstrate that p32/C1qbp is an important regulator of IMQ-induced DC activation, both in vivo and in vitro. We also found that p32/C1qbp-deficient DCs exhibited impaired production of IL-1β, IL-23, and mitochondrial reactive oxygen species (mtROS) after IMQ stimulation. Because the inhibition of mtROS suppressed IMQ-induced DC activation and psoriatic inflammation, we presume that p32/C1qbp and mtROS can serve as therapeutic targets in psoriasis.

KLK6 protease accelerates skin tumor formation and progression.

Kallikrein-related peptidase 6 (KLK6) is a serine protease that is aberrantly altered in various types of cancer, but its role in non-melanoma skin cancer has not been investigated. KLK6 is active in epidermis and has been linked to normal skin differentiation. Thus, we investigated whether it could be implicated in skin tumorigenesis in vivo. Carcinogenesis was induced in Klk6-/- mice by epidermal application of 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol 13-acetate (DMBA/TPA), and multistage skin tumor development and progression was monitored closely until squamous cell carcinomas (SCCs) and invasive tumors formed. Klk6-/- (but also Klk6+/-) mice were highly resistant to tumor growth/development manifested by their highly diminished numbers and delayed onset of tumors compared with wild-type (wt) mice. Histological analyses of the few tumors that developed in Klk6-/- after prolonged (>1 year) chemical challenge revealed that these were mainly benign papillomas, whereas in wt mice tumors progressed to SCCs. Inflammation was attenuated in Klk6-/- skin following chronic exposure to TPA, indicated by markedly low expression of proinflammatory cytokines, in direct contrast to wt. Further, in Klk6-/- mice, the ability of implanted nascent PDVC57 skin cancer cells to form tumors was highly diminished. Our study identified KLK6 as a new tumor-promoting factor of early skin cancer and suggested that KLK6 is an important molecular link in the development of skin inflammation and in tumor-promoting inflammatory processes.

INTERDEPENDENCE OF VIOLATIONS OF CYTOKINE PEPTIDE SIGNAL MOLECULES IN PATIENTS WITH ACNE

Despite numerous studies of etiology and pathogenesis of acne, this disease is one of the extended ones dermatoses worldwide among young people. One of the insufficiently solved problems of acne is to establish the role of peptide signaling molecules in the mechanisms of sebum formation and inflammation of the skin. The aim is to investigate the content of cytokine peptide signal molecules of various functional groups in the blood of patients with acne and their interrelations and to clarify their role in the process of inflammation of the sebaceous complex in this dermatosis. The study included 117 patients with acne, who determined the serum levels of the tumor necrosis factor-alpha (TNF α ), interleukin-6 (IL-6), transforming growth factor-beta (TGF β 1), interferon-gamma (IFN γ ) ELISA using appropriate reagent kits from Bender MedSystem, Vienna (AT). The statistical processing of the research data was carried out using the licensed program STATISTICA®6.0. In all patients with acne, an acute-inflammatory papulopustular form of dermatosis was diagnosed. ELISA results established the presence of all patients with changes in serum levels of the investigated peptide molecules (cytokines) of varying severity, which differed significantly from those of the control group. E stablished correlation links between the blood levels of the cytokine peptide signal molecules studied (TNF α with IL-6 and TGF β 1, IL-6 with TGF β 1 and IFN γ , TGF β 1 with IFN γ ), confirms the presence of cellular and intercellular and molecular interactions of cytokines in the inflammatory process of the sebaceous complex in patients with acne, causing the formation of immune responses aimed at restoring physiological morphological and functional parameters of the skin and its appendages. Cytokines of various functional groups influence the clinical manifestations of acne: the appearance of comedones (IL-1), the development of skin inflammation in the sebaceous gland (TNFα, IFNγ), the presence of complicated deep forms of acne (TGFβ1), which is due to their complex effect on a many of pathophysiological processes in this dermatosis (initiation of cell damage, atrophy, dedifferentiation, etc.). Keywords: acne, interleukin-6, tumor necrosis factor-alpha, interferon-gamma, transforming growth factor-beta1. В. В. Бочарова, кандидат медичних наук. Взаємозалежність порушень цитокінових пептидних сигнальних молекул у хворих на вугрову хворобу / Одеський національний медичний університет, Україна, Одеса Незважаючи на численні дослідження етіології та патогенезу вугрової хвороби це захворювання є одним із найпоширеніших дерматозів в усьому світі серед осіб молодого віку. Однією з недостатньо вирішених проблем вугрової хвороби є з’ясування ролі пептидних сигнальних молекул в механізмах себогенезу та запалення шкіри Мета роботи – дослідити вміст у крові хворих на вугрову хворобу цитокінових пептидних сигнальних молекул різних функціональних груп та їх взаємозв’язки і з’ясувати їх роль у процесі запалення полісебаційного комплексу при цьому дерматозі. В дослідження було включено 117 хворих на вугрову хворобу, яким було проведено дослідження вмісту у сироватці крові фактору некрозу пухлин-альфа ( TNF α), інтерлейкіну-6 ( IL -6), трансформуючого факору росту-бета ( TGFβ 1 ), інтерферону-гама ( IFNγ ) методом імуноферментного аналізу із використанням відповідних наборів реактивів фірми «Bender MedSystem», Vienna ( AT ). Статистичну обробку даних дослідження проводили за допомогою ліцензованої програми «STATISTICA ® 6.0». У всіх обстежених хворих на вугрову хворобу було діагностовано гострозапальну папуло-пустульозну форму дерматозу. Результати імуноферментного аналізу дозволили встановити наявність у всіх хворих змін вмісту у сироватці крові хворих на вугрову хворобу досліджених пептидних молекул (цитокінів) різного ступеня виразності, що достовірно відрізнялися від аналогічних досліджених показників контрольної групи. Встановлено значимі кореляційні взаємозв’язки між вмістом у крові досліджених пептидних сигнальних молекул ( TNF α з IL -6 і TGFβ 1 ; IL -6 з TGFβ 1 і IFNγ ; TGFβ 1 з IFNγ , що підтверджує наявність висококомунікативних міжклітинних та молекулярних взаємодій цитокінів при запальному процесі полісебаційного комплексу у хворих на вугрову хворобу, що обумовлює формування імунних реакцій, спрямованих на відновлення фізіологічних морфофункціональних параметрів шкіри та її придатків. Цитокіни різних функціональних груп впливають на особливості клінічних проявів вугрової хвороби – появу комедонів ( IL -1), розвиток запалення шкіри в області сальних залоз ( TNFα , IFNγ ), наявність ускладнених глибоких форм акне ( TGFβ 1), що обумовлено їх комплексним впливом на низку патофізіологічних процесів при цьому дерматозі (ініціація пошкодження клітин, атрофія, дедиференціація та ін.). Ключові слова: вугрова хвороба, інтерлейкін-6, фактор некрозу пухлин-альфа, інтерферон-гамма, трансформуючий фактор росту-бета1.

Myeloid but not plasmacytoid blood DCs possess Th1 polarizing and Th1/Th17 recruiting capacity in psoriasis

Psoriasis is a common inflammatory skin disease and dendritic cells (DCs) play crucial role in the development of skin inflammation. Although the characteristics of skin DCs in psoriasis are well defined, less is known about their peripheral blood precursors. Our aim was to characterize the phenotypic features as well as the cytokine and chemokine production of CD1c+ myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the blood samples of psoriatic patients. Blood DCs were isolated by using a magnetic separation kit, and their intracytoplasmic cytokine production and CD83/CD86 maturation/activation marker expression were investigated by 8-colour flow cytometry. In CD1c+ mDCs the intracellular productions of Th1, Th2, Th17, Th22 and Treg polarizing cytokines were examined simultaneously, whereas in pDCs the amounts of IFNα as well as IL-12, IL-23 and IL-6 were investigated. The chemokine production of both DC populations was investigated by flow-cytometry and ELISA. According to our results psoriatic CD1c+ mDCs were in a premature state since their CD83/CD86 maturation/activation marker expression, IL-12 cytokine, CXCL9 and CCL20 chemokine production was significantly higher compared to control cells. On the other hand, blood pDCs neither produced any of the investigated cytokines and chemokines nor expressed CD83/CD86 maturation/activation markers. Our results indicate that in psoriasis not only skin but also blood mDCs perform Th1 polarizing and Th1/Th17 recruiting capacity, while pDCs function only in the skin milieu.

334 Role of RIP kinase signalling in the development of skin inflammation in mice with keratinocyte-specific IKK deficiency

334 Role of RIP kinase signalling in the development of skin inflammation in mice with keratinocyte-specific IKK deficiency

Pathogenesis and targeted treatment of skin injury in SLE.

Skin is the second most common organ (after the kidney) to be affected in patients with systemic lupus erythematosus (SLE), yet the aetiology of skin injury and the mechanisms involved in the development of dermal manifestations of SLE remain unclear. Ultraviolet light (UV), immune cells, cytokines and deposition of immunoglobulins all seem to have a role in the development of skin inflammation and damage in SLE. UV represents the most important environmental factor, and exposure to UV triggers the development of skin lesions in areas where immunoglobulin has been deposited and various other components of the immune system have accumulated. In addition, a number of intracellular kinases and transcription factors have also been demonstrated to be involved in the generation of skin lesions in lupus-prone mice. These molecules can be targeted by small-molecule inhibitors, leading to the prospect that treatments suitable for topical application, and with limited adverse effects, could be developed. Further studies to eliminate the burden of skin inflammation in patients with SLE are clearly required.

Basophils regulate the recruitment of eosinophils in a murine model of irritant contact dermatitis

Although eosinophils have been detected in several human skin diseases in the vicinity of basophils, how eosinophils infiltrate the skin and the role of eosinophils in the development of skin inflammation have yet to be examined. Using murine irritant contact dermatitis (ICD) as a model, we sought to clarify the roles of eosinophils in ICD andthe underlying mechanism of eosinophil infiltration of the skin. We induced croton oil-induced ICD in eosinophil-deficient ΔdblGATA mice with or without a reactive oxygen species (ROS) inhibitor. We performed cocultivation with fibroblasts and bone marrow-derived basophils and evaluated eosinophil migration using a chemotaxis assay. ICD responses were significantly attenuated in the absence of eosinophils or by treatment with the ROS inhibitor. ROS was produced abundantly by eosinophils, and both basophils and eosinophils were detected in human and murine ICD skin lesions. In coculture experiments, basophils attracted eosinophils, especially in the presence of fibroblasts. Moreover, basophils produced IL-4 and TNF-α in contact with fibroblasts and promoted the expression of eotaxin/CCL11 from fibroblasts invitro. Eosinophils mediated the development of murine ICD, possibly through ROS production. Recruitment of eosinophils into the skin was induced by basophils in cooperation with fibroblasts. Our findings introduce the novelconcept that basophils promote the recruitment of eosinophils into the skin through fibroblasts in the developmentof skin inflammation.

Identification of anti-allergic effect of Clonorchis sinensis-derived protein venom allergen-like proteins (CsVAL)

Previous studies demonstrated that Clonochis sinensis-derived crude antigens suppress development of allergic responses. We investigated the effects of C. sinensis venom allergen-like (CsVAL) proteins on immune-modulating activities in allergic inflammatory response. Using RBL-2H3 rat mast cells, we demonstrated that CsVAL inhibits antigen-induced β-hexosaminidase release from immunoglobulin E-sensitized RBL-2H3 cells, and this inhibitory activity occurs by suppressing Lyn phosphorylation and intracellular reactive oxygen species production. In addition, CsVAL peptide treatment inhibits activation of protein kinase C-α and extracellular signal-regulated kinase 1/2, which are involved in degranulation of immunoglobulin E-sensitized mast cells. Furthermore, immunization with CsVAL suppressed development of skin inflammation by assessing ear thickness and cutaneous infiltration by eosinophils and mast cells in oxazolone-induced contact hypersensitivity in vivo mouse model. These results suggest that CsVAL is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases.

Role of neuromediators in the development of skin inflammation in patients with atopic dermatitis

Neurotransmitters such as neuropeptides and neurotrophins can have an effect on the development of a skin inflammatory reaction and itching as well as condition of nerve fibers. Goal. To assess the expression of neuropeptides and neurotrophins in the skin of patients with atopic dermatitis. Materials and methods. Expression of neuropeptides of substance P and SP-R receptor, calcitonin gene-related peptide (CGRP) and CGRP-R receptor, neurotrophin (nerve growth factor) and TrkA receptor as well as amphiregulin enhancing the growth of nerve fibers and semaphorin-3A terminating the growth of nerve fibers was determined in the skin of patients with atopic dermatitis based on the immunohistochemistry analysis method. Expression of protein PGP9.5 being a marker of nerve fibers was also determined. Results. The authors discovered penetration of nerve fibers expressing substance P and CGRP into the epidermis in patients with atopic dermatitis. Expression of the nerve growth factor and amphiregulin was discovered in epidermis but no expression of semaphorin-3A was discovered. Conclusion. Nerve fibers expressing neuropeptides such as substance P and CGRP can penetrate into the epidermis in patients with atopic dermatitis, which can maintain the inflammatory reaction and itching in such patients. Expression of the growth factors (nerve growth factor and amphiregulin) can contribute to the growth of nerve fibers and their penetration into epidermis against the background of the absence of any expression of semaphorin-3A inhibiting their growth.

The Adaptor Protein FADD Protects Epidermal Keratinocytes from Necroptosis In Vivo and Prevents Skin Inflammation

Epidermal keratinocytes provide an essential structural and immunological barrier forming the first line of defense against potentially pathogenic microorganisms. Mechanisms regulating barrier integrity and innate immune responses in the epidermis are important for the maintenance of skin immune homeostasis and the pathogenesis of inflammatory skin diseases. Here, we show that epidermal keratinocyte-restricted deficiency of the adaptor protein FADD (FADD(E-KO)) induced severe inflammatory skin lesions in mice. The development of skin inflammation in FADD(E-KO) mice was triggered by RIP kinase 3 (RIP3)-mediated programmed necrosis (termed necroptosis) of FADD-deficient keratinocytes, which was partly dependent on the deubiquitinating enzyme CYLD and tumor necrosis factor (TNF)-TNF receptor 1 signaling. Collectively, our findings provide an invivo experimental paradigm that regulation of necroptosis in keratinocytes is important for the maintenance of immune homeostasis and the prevention of chronic inflammation in the skin.

Dual Face Apoptotic Machinery: From Initiator of Apoptosis to Guardian of Necroptosis

In this issue of Immunity, Bonnet etal. (2011) show that skin-specific ablation of the adaptor protein FADD sensitizes keratinocytes to RIPK3-dependent necrotic cell death, which leads to severe skin inflammation.

Histamine receptor H1 signaling on dendritic cells plays a key role in the IFN-γ/IL-17 balance in T cell–mediated skin inflammation

The diverse effects of histamine on immune regulation are a result of the differential expression and regulation of 4 histamine receptors. Many of the immediate allergic and inflammatory actions of histamine are mediated via the type 1 receptor (H1R). We hypothesized that H1R was involved in the fine-tuning of the initiation of T cell-mediated skin pathology-that is, dermatitis. The impact of the H1R invalidation on the development of skin inflammation was analyzed in a mouse model of atopic dermatitis. We show that H1r(-)/(-) mice developed reduced allergen-specific skin lesions. Lack of H1R expression on dendritic cells (DCs) led to diminished IL-12, upregulated IL-23, and IL-6 production upon allergen stimulation. H1R engagement on dendritic cells was necessary for DC activation and subsequent priming of effector IFN-γ(+)CD8(+) T cells. We demonstrate here that H1R blockade on DCs promotes generation of noneffector IL-17(+)CD8(+) T cells that are unable to initiate the skin inflammation. Our data identify that histamine signaling through the H1R on DCs is an important early event conditioning the quality of the skin effector immune response.

Phospholipase Cε as a potential molecular target for anti-inflammatory therapy and cancer prevention

Phospholipase Ce (PLCe), encoded by PLCE1, is the phosphoinositide-specific PLC regulated by the ras proto-oncogene product Ras and its relative Rap1. Like other PLC isoforms, PLCe catalyzes hydrolysis of phosphatidylinositol 4,5-bisphosphate to yield second messengers, diacylglycerol and inositol 1,4,5-trisphosphate. To understand the physiological function of PLCe, we have created and analyzed genetically-modified mice in which PLCe is inactivated or overproduced. PLCe knockout (KO) mice are resistant to two-stage skin chemical carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and to intestinal tumorigenesis caused by the loss-of-function mutation of the APC tumor suppressor gene. In PLCe KO mice, inflammation, such as that induced by a single application of PMA, that associated with tumorigenesis, and that in the elicitation phase of allergic contact hypersensitivity, is also attenuated as compared to that in wild-type mice. Conversely, overexpression of PLCe in the epidermis results in the development of skin inflammation that partly shares the features with human psoriasis. In this article, we summarize the data showing the role of PLCe in tumorigenesis and inflammation and discuss the future directions of the study of PLCe for the development of therapies to control inflammation and to prevent cancer progression.

Overexpression of phospholipase Cε in keratinocytes upregulates cytokine expression and causes dermatitis with acanthosis and T‐cell infiltration

Phospholipase Cε (PLCε) is an effector of Ras and Rap small GTPases. We showed previously using PLCε-deficient mice that PLCε plays a critical role in activation of cytokine production in non-immune skin cells in a variety of inflammatory reactions. For further investigation of its role in inflammation, we created transgenic mice overexpressing PLCε in epidermal keratinocytes. The resulting transgenic mice spontaneously developed skin inflammation as characterized by formation of adherent silvery scales, excessive growth of keratinocytes, and aberrant infiltration of immune cells such as T cells and DC. Development of the skin symptoms correlated well with increased expression of factors implicated in human inflammatory skin diseases, such as IL-23, in keratinocytes, and with the accumulation of CD4(+) T cells producing IL-22, a potent inducer of keratinocyte proliferation. Intradermal injection of a blocking antibody against IL-23 as well as treatment with the immunosuppressant FK506 reversed these skin phenotypes, which was accompanied by suppression of the IL-22-producing T-cell infiltration. These results reveal a crucial role of PLCε in the development of skin inflammation and suggest a mechanism in which PLCε induces the production of cytokines including IL-23 from keratinocytes, leading to the activation of IL-22-producing T cells.

Skin Exposure to Weak and Moderate Contact Allergens Induces IFNγ Production by Lymph Node Cells of CD4+ T-Cell-Depleted Mice

Allergic contact dermatitis (ACD) is mediated by hapten-specific CD8+ T cells and downregulated by CD4+ T cells. We have recently shown in a model of ACD to weak haptens that priming of IFNgamma-producing CD8+ T cells and the development of skin inflammation could be obtained in mice deficient in CD4+ T cells. Here we show that IFNgamma production by lymph node (LN) cells draining the site of skin sensitization of CD4+ T-cell-deficient mice is a marker of the sensitizing properties of weak haptens. LN cells from mice sensitized as in the classical local lymph node assay (LLNA) were recovered at day 5, then cultured for 20 hours in the presence of submitogenic doses of phytohemagglutinin, and finally tested for the production of IFNgamma. Results show that: (i) production of INFgamma by LN cells was induced by weak and moderate allergens in a dose-dependent fashion; (ii) the magnitude of IFNgamma production paralleled the sensitizing properties of allergens allowing to classify them as moderate or weak haptens; (iii) chemicals without sensitizing properties were unable to stimulate IFNgamma production by LN cells. Therefore, the IFNgamma LLNA appears as a sensitive, specific, and robust assay to detect weak contact allergens.

Is there a role for mast cells in psoriasis?

Mast cells have traditionally been considered as effector cells in allergy but during the last decade it has been realized that mast cells are essentially involved in the mechanisms of innate and acquired immunity. Upon activation by anaphylactic, piecemeal degranulation or degranulation-independent mechanisms mast cells can secrete rapidly or slowly a number of soluble mediators, such as serine proteinases, histamine, lipid-derived mediators, cytokines, chemokines and growth factors. Mast cells can express cell surface co-stimulatory receptors and ligands, and they can express MHC class II molecules and thereby present antigens. These soluble factors and cell surface molecules can interact with other cells, such as endothelial cells, keratinocytes, sensory nerves, neutrophils, T cell subsets and antigen presenting cells which are essential effectors in the development of skin inflammation. Besides promoting inflammation, mast cells may attempt in some circumstances to suppress the inflammation and epidermal growth but the regulation between suppressive and proinflammatory mechanisms is unclear. Psoriasis is characterized by epidermal hyperplasia and chronic inflammation where tryptase- and chymase-positive MC(TC) mast cells are activated early in the developing lesion and later the cells increase in number in the upper dermis with concomitant expression of cytokines and TNF superfamily ligands as well as increased contacts with neuropeptide-containing sensory nerves. Due to the intimate involvement of mast cells in immunity and chronic inflammation the role of mast cells in psoriasis is discussed in this review.

Inhibitory Effect of a Potent and Selective Cytosolic Phospholipase A2α Inhibitor RSC-3388 on Skin Inflammation in Mice

Cytosolic phospholipase A₂α (cPLA₂α) preferentially hydrolyzes membrane phospholipids containing arachidonic acid, resulting in the biosynthesis of eicosanoids such as prostaglandins and leukotrienes. To examine the contribution of cPLA₂α to skin inflammation, we evaluated the effect of (E)-N-[(2S,4R)-4-[N-(biphenyl-2-ylmethyl)-N-2-methylpropylamino]-1-[2-(2,4-difluorobenzoyl)benzoyl]pyrrolidin- 2-yl]methyl-3-[4-(2,4-dioxothiazolidin-5-ylidenemethyl) phenyl]acrylamide (RSC-3388), a potent and selective cPLA₂α inhibitor, on 2,4,6-trinitro-1-chlorobenzene (TNCB)-induced ear inflammation and mite antigen-induced dermatitis in mice. Topical application of RSC-3388 showed a significant inhibitory activity against TNCB-induced ear swelling and eicosanoid production in mice. Comprehensive expression analysis using Gene-Chip technology and subsequent experiments concerning mRNA and protein expression demonstrated that RSC-3388 clearly reduced the levels of interleukin-1β, macrophage inflammatory protein-1α (MIP-1α) and MIP-1β in a TNCB-induced mouse model. In addition, RSC-3388 ointment significantly alleviated atopic dermatitis-like skin lesions induced by repeated application of mite antigen. Furthermore, increased expression of cPLA₂α, assessed by anti-phospho-cPLA₂α antibody, was observed in the skin lesions of mite-antigen-induced dermatitis. These results indicate that cPLA₂α is involved in the development of skin inflammation in mice, and RSC-3388 is expected to be useful for the treatment of inflammatory skin disorders such as atopic dermatitis.