Hitokazu Esaki

T cell-specific overexpression of interleukin-27 receptor α subunit (WSX-1) prevents spontaneous skin inflammation in MRL/lpr mice

Background  Interleukin (IL)‐27 and WSX‐1, the receptor α‐specific subunit, have been shown to play important roles in initiating Th1 responses and in inducing immune modulation, and the immunosuppressive effect of IL‐27 appears to be exerted via suppression of IL‐10 and IL‐17, which may participate in the pathogenesis of human systemic lupus erythematosus (SLE).

Topical application of PPARα (but not β/δ or γ) suppresses atopic dermatitis in NC/Nga mice

Peroxisome proliferator‐activated receptors (PPARs) are nuclear receptors, which regulate not only adipogenesis and proliferation/differentiation but also the immune response of cells. Because topical application of the activators of some PPAR isoforms improved clinical symptoms in patients with atopic dermatitis (AD), we investigated the role of PPAR activators using a murine AD model in NC/Nga mice; to the best of our knowledge, this has not been previously reported.

Scratching behavior does not necessarily correlate with epidermal nerve fiber sprouting or inflammatory cell infiltration.

BACKGROUND Increased sprouting of epidermal nerve fibers of lesional skin are thought to be associated with persistent pruritus in chronic inflammatory dermatitis such as atopic dermatitis as supported by a murine study using tacrolimus (or FK506: FK) which was shown to inhibit both epidermal sprouting of nerves and scratching behavior or by immunohistochemical observations of lesional skin in the patients with atopic dermatitis or prurigo, etc. OBJECTIVES To examine a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) inhibitor (CX-659S: CX) for a possible anti-pruritic property in vivo since some MEK1/2 inhibitors have been reported to inhibit neurite growth in vitro. METHODS CX, FK and corticosteroids (betamethasone valerate: BV) were topically applied on inflamed skin in a mouse model of chronic dermatitis using repetitive hapten painting to examine anti-pruritic property and anti-inflammatory effects. Scratching behaviors were assessed using MicroAct automatic measuring system, and epidermal sprouting of nerves and skin inflammation was assessed histologically. RESULTS FK significantly decrease scratching behavior, but CX and BV failed to do so despite of their ability to significantly inhibit epidermal nerve fiber sprouting and skin inflammation, respectively. In addition, CX+BV mixture synergistically inhibited epidermal nerve fiber sprouting and skin inflammation even more potently than FK without decreasing scratching behavior. CONCLUSIONS These findings suggest that the scratching behavior does not necessarily correlate with epidermal nerve fiber sprouting or inflammatory cell infiltration.

Antioxidant Opuntia ficus-indica Extract Activates AHR-NRF2 Signaling and Upregulates Filaggrin and Loricrin Expression in Human Keratinocytes

UNLABELLED Opuntia ficus-indica (OFI) is a cactus species widely used as an anti-inflammatory, antilipidemic, and hypoglycemic agent. It has been shown that OFI extract (OFIE) inhibits oxidative stress in animal models of diabetes and hepatic disease; however, its antioxidant mechanism remains largely unknown. In this study, we demonstrated that OFIE exhibited potent antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the downstream antioxidant enzyme NAD(P)H quinone oxidoreductase 1 (NQO1), which inhibited the generation of reactive oxygen species in keratinocytes challenged with tumor necrosis factor α or benzo[α]pyrene. The antioxidant capacity of OFIE was canceled in NRF2 knockdown keratinocytes. OFIE exerted this NRF2-NQO1 upregulation through activation of the aryl hydrocarbon receptor (AHR). Moreover, the ligation of AHR by OFIE upregulated the expression of epidermal barrier proteins: filaggrin and loricrin. OFIE also prevented TH2 cytokine-mediated downregulation of filaggrin and loricrin expression in an AHR-dependent manner because it was canceled in AHR knockdown keratinocytes. Antioxidant OFIE is a potent activator of AHR-NRF2-NQO1 signaling and may be beneficial in treating barrier-disrupted skin disorders.

Epidemiology of atopic dermatitis in Japan

Atopic dermatitis (AD) is a common, chronic or chronically relapsing, severely pruritic and eczematous skin disease. AD is the second most frequently observed skin disease in dermatology clinics in Japan. Prevalence of childhood AD is 12–13% in mainland Japan; however, it is only half that (~6%) in children from Ishigaki Island, Okinawa. Here, we summarize the prevalence, incidence and spontaneous regression of AD and the relation of AD to other allergic diseases from previous reports. We also refer to our recent findings from a population cohort study on Ishigaki Island, Okinawa.

Correlation between serum thymus and activation-regulated chemokine levels and stratum corneum barrier function in healthy individuals and patients with mild atopic dermatitis

BACKGROUND Serum thymus and activation-regulated chemokine (TARC) levels closely reflect the disease activity of atopic dermatitis (AD). AD is characterized by impaired epidermal barrier function and atopic dry skin. However, dry skin is also a very common problem in healthy individuals. OBJECTIVE To investigate the relationship between serum TARC levels and epidermal barrier function in healthy subjects and patients with mild AD. METHODS This study included 2 groups, 121 healthy subjects (healthy group) and 66 patients with mild AD (mild AD group). Barrier function was assessed by transepidermal water loss (TEWL) and stratum corneum hydration (SCH). RESULTS Significantly elevated serum TARC levels and TEWL values and significantly decreased SCH values were detected in the mild AD group compared to those in the healthy group. In the mild AD group, serum TARC levels were significantly correlated with TEWL values and were inversely correlated with SCH values. Importantly, serum TARC levels were also inversely correlated with SCH values in the healthy controls. TEWL values in the healthy group tended to be correlated with TARC levels but did not reach statistical significance. CONCLUSION Together with TEWL and SCH, serum TARC level is a useful biomarker, reflecting impairment of epidermal function in AD patients as well as healthy subjects.

Genetic polymorphisms in the IL22 gene are associated with psoriasis vulgaris in a Japanese population

individuals and the features of inflammation are characterized by tumor necrosis factor (TNF)-a dependence and exaggerated helper T cell 1 (Th1) and 17 (Th17) activation. Interleukin (IL)-22 is an IL10 family cytokine member produced by Th17 cells and plays a role in the promotion of inflammation and tissue repair at barrier surfaces [2]. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation [3], and circulating IL-22 levels are significantly higher in psoriatic patients than in normal subjects [4,5]. Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that is basically considered to be a Th-2 type disease. However, a recent study suggests a possible role of Th17 cells in AD [6]. The study has shown that the number of Th17 cells is increased in the peripheral blood and acute lesional skin of AD and that IL-17 and IL-22 synergistically enhance the production of IL-8 from keratinocytes [6]. Since there are few genetic studies of the polymorphisms of IL22 in populations of Asian and European ancestry, we conducted association studies to assess whether IL22 gene variants contribute to the susceptibility to PsV or AD in a Japanese population. We recruited a total of 236 patients with PsV (mean age 53, 11– 85 years, male:female ratio = 1.0:2.8), and all subjects were diagnosed by clinical and histopathological findings. A total of 916 patients with AD (mean age 30, 3–77 years, male:female ratio = 1.0:2.2) and 844 controls (mean age 50, 20–75 years, male:female ratio = 1.0:1.3) were recruited as described [7]. Patients with AD were diagnosed according to the criteria of Hanifin and Rajka, and control subjects were never diagnosed with AD or PsV. All individuals were unrelated Japanese and gave written informed consent to participate in the study. The study was approved by the ethical committees at the Institute of Physical and Chemical Research (RIKEN), the University of Tokyo and the Jikei University School of Medicine. Genomic DNA was prepared in accordance with standard protocols. We resequenced the IL22 gene regions with genomic DNA from 36 individuals and identified a total of 32 polymorphisms (Table 1). We next examined the linkage disequilibrium (LD) between identified SNPs (Fig. S1). Pairwise LD coefficients D0 and r were calculated among the 24 SNPs with minor allele frequencies (MAF) of greater than 5% using Haploview 4.2 (http://www.broad. mit.edu/mpg/haploview/). We selected a total of 11 tag SNPs for association studies using tagger in Haploview 4.2, and the 11 tag

Variants of C-C Motif Chemokine 22 (CCL22) Are Associated with Susceptibility to Atopic Dermatitis: Case-Control Studies

Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1st population, 916 cases and 1,032 controls; 2nd population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10−6; OR, 0.74; 95% CI, 0.65–0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.

Levels of immunoglobulin E specific to the major food allergen and chemokine (C-C motif) ligand (CCL)17/thymus and activation regulated chemokine and CCL22/macrophage-derived chemokine in infantile atopic dermatitis on Ishigaki Island.

Atopic dermatitis (AD) is a multifactorial T‐helper (Th)2‐mediated skin disease frequently associated with elevated serum immunoglobulin (Ig)E and food allergy is also a Th2‐ and IgE‐mediated adverse immunological reaction. Our previous study indicated the relation of egg allergy history and disease severity of AD. Thus, the purpose of the study was to investigate the levels of IgE specific to major food allergens (egg, milk, wheat) and Th2 chemokines (chemokine [C‐C motif] ligand [CCL]17/thymus and activation regulated chemokine [TARC] and CCL22/macrophage‐derived chemokine [MDC]) and the relationship between them. A total of 743 nursery school children were enrolled. Dermatologist‐based physical examination and a questionnaire survey were also conducted. Significantly increased levels of disease severity markers (CCL17/TARC and CCL22/MDC) were confirmed in children with AD. The levels of CCL22/MDC in all of the children were markedly high compared with those reported in adults. IgE specific to egg white, ovomucoid, wheat and mite antigen were significantly higher in the AD group than in the non‐AD group. Among them, IgE specific to egg allergens were well associated with disease severity markers, and IgE specific to ovomucoid seemed particularly well correlated with the presence of egg allergy history. In conclusion, the markedly high level of CCL22/MDC in children as compared with those reported in adults may partly explain the AD‐prone nature of children and their spontaneous remission afterwards. Mild but significant correlation of IgE specific to egg allergens and Th2 chemokines may explain correlation of disease severity and comorbidity of egg allergy in our previous study.

Genetic polymorphism in the TRAF3IP2 gene is associated with psoriasis vulgaris in a Japanese population.

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