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Journal: The Journal of investigative dermatology

348

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that results in significant morbidity. A hallmark of AD is disruption of the critical barrier function of upper epidermal layers, causatively linked to environmental stimuli, genetics, and infection, and a critical current target for the development of new therapeutic and prophylactic interventions. Staphylococcus aureus is an AD-associated pathogen producing virulence factors that induce skin barrier disruption in vivo and contribute to AD pathogenesis. We show, using immortalized and primary keratinocytes, that S. aureus protease SspA/V8 is the dominant secreted factor (in laboratory and AD clinical strains of S. aureus) inducing barrier integrity impairment and tight junction damage. V8-induced integrity damage was inhibited by an IL-1β-mediated mechanism, independent of effects on claudin-1. Induction of keratinocyte expression of the antimicrobial/host defense peptide human β-defensin 2 (hBD2) was found to be the mechanism underpinning this protective effect. Endogenous hBD2 expression was required and sufficient for protection against V8 protease-mediated integrity damage, and exogenous application of hBD2 was protective. This modulatory property of hBD2, unrelated to antibacterial effects, gives new significance to the defective induction of hBD2 in the barrier-defective skin lesions of AD and indicates therapeutic potential.

Concepts: Inflammation, Bacteria, Microbiology, Staphylococcus aureus, Skin, Protease, Virulence factor, Atopic dermatitis

140

Tyrosinase is the rate-limiting enzyme of melanin production and, accordingly, is the most prominent target to inhibit hyperpigmentation. Numerous tyrosinase inhibitors have been identified, but most of those lack clinical efficacy because they were identified using mushroom tyrosinase as the target. Therefore, we used recombinant human tyrosinase to screen a library of 50,000 compounds and compared the active screening hits with well-known whitening ingredients. Hydroquinone and its derivative arbutin only weakly inhibited human tyrosinase with a half-maximal inhibitory concentration (IC50) in the millimolar range, while kojic acid showed a weak efficacy (IC50 > 400 μM). The most potent inhibitors of human tyrosinase identified in this screen were resorcinyl-thiazole derivatives, especially the newly identified thiamidol (isobutylamido thiazolyl resorcinol), which had an IC50 of 1.1 μM. In contrast, thiamidol only weakly inhibited mushroom tyrosinase (IC50: 108 μM). In melanocyte cultures, thiamidol strongly but reversibly inhibited melanin production (IC50: 0.9 μM) while hydroquinone irreversibly inhibited melanogenesis (IC50: 16.3 μM). Clinically, thiamidol visibly reduced the appearance of age spots within 4 weeks and after 12 weeks some age spots were indistinguishable from the normal adjacent skin. The full potential of thiamidol to reduce hyperpigmentation of human skin needs to be explored in future studies.

Concepts: Skin, Enzyme inhibitor, Inhibitor, Xanthine oxidase inhibitor, Human skin color, Melanocyte, Tyrosinase, Skin whitening

82

Earwax type and axillary odor are genetically determined by rs17822931, a single-nucleotide polymorphism (SNP) located in the ABCC11 gene. The literature has been concerned with the Mendelian trait of earwax, although axillary odor is also Mendelian. Ethnic diversity in rs17822931 exists, with higher frequency of allele A in east Asians. Influence on deodorant usage has not been investigated. In this work, we present a detailed analysis of the rs17822931 effect on deodorant usage in a large (N∼17,000 individuals) population cohort (the Avon Longitudinal Study of Parents and Children (ALSPAC)). We found strong evidence (P=3.7 × 10(-20)) indicating differential deodorant usage according to the rs17822931 genotype. AA homozygotes were almost 5-fold overrepresented in categories of never using deodorant or using it infrequently. However, 77.8% of white European genotypically nonodorous individuals still used deodorant, and 4.7% genotypically odorous individuals did not. We provide evidence of a behavioral effect associated with rs17822931. This effect has a biological basis that can result in a change in the family’s environment if an aerosol deodorant is used. It also indicates potential cost saving to the nonodorous and scope for personalized genetics usage in personal hygiene choices, with consequent reduction of inappropriate chemical exposures for some.Journal of Investigative Dermatology advance online publication, 17 January 2013; doi:10.1038/jid.2012.480.

Concepts: DNA, Gene, Genetics, Genotype, Allele, Evolution, Biology, Mendelian inheritance

79

The diverse immunomodulatory effects of vitamin D are increasingly being recognized. However, the ability of oral vitamin D to modulate acute inflammation in vivo has not been established in humans. In a double-blinded, placebo-controlled interventional trial, twenty healthy adults were randomized to receive either placebo or a high dose of vitamin D3 (cholecalciferol) one hour after experimental sunburn induced by an erythemogenic dose of ultraviolet radiation. Compared to placebo, participants receiving vitamin D3 (200,000 IU) demonstrated reduced expression of pro-inflammatory mediators TNF-α (p=0.04) and iNOS (p=0.02) in skin biopsy specimens 48 hours after experimental sunburn. A blinded, unsupervised hierarchical clustering of participants based on global gene expression profiles revealed that participants with significantly higher serum vitamin D3 levels after treatment (p=0.007) demonstrated increased skin expression of the anti-inflammatory mediator arginase-1 (p=0.005), and a sustained reduction in skin redness (p=0.02), correlating with significant expression of genes related to skin barrier repair. In contrast, participants with lower serum vitamin D3 levels had significant expression of pro-inflammatory genes. Together the data may have broad implications for the immunotherapeutic properties of vitamin D in skin homeostasis, and implicate arginase-1 up regulation as a previously unreported mechanism by which vitamin D exerts anti-inflammatory effects in humans.

Concepts: DNA, Vitamin D, Gene, Genetics, Gene expression, Cancer, Ultraviolet, Organism

72

Mitochondria are the principal destination for labile iron (LI), making these organelles particularly susceptible to oxidative damage upon exposure to ultraviolet A (UVA, 320-400 nm), the oxidizing component of sunlight. The LI-mediated oxidative damage caused by UVA to mitochondria leads to necrotic cell death via ATP depletion. Therefore targeted removal of mitochondrial LI via highly specific tools from these organelles may be an effective approach to protect the skin cells against the harmful effects of UVA. In this work, we designed a mitochondria-targeted hexadentate (tricatechol-based) iron chelator linked to mitochondria- homing SS-like peptides. The photoprotective potential of this compound against UVA-induced oxidative damage and cell death was evaluated in cultured primary skin fibroblasts. Our results show that this compound provides unprecedented protection against UVA-induced mitochondrial damage, ATP depletion and the ensuing necrotic cell death in skin fibroblasts and this effect is fully related to its potent iron-chelating property in the organelle. This mitochondria-targeted iron chelator has therefore promising potential for skin photoprotection against the deleterious effects of UVA component of sunlight.

Concepts: DNA, Photosynthesis, Cell, Adenosine triphosphate, Mitochondrion, Cytosol, Organelle, Cell biology

60

The factors that contribute to the development of psoriatic arthritis (PsA) among patients with psoriasis are not well known; however, systemic inflammation is believed to be important. On the basis of recent laboratory work demonstrating that major depressive disorder (MDD) is associated with increased systemic inflammation, we hypothesized that patients with psoriasis who develop MDD are at increased risk of subsequently developing PsA. We utilized The Health Improvement Network, a primary care medical records database, to identify 73,447 individuals with psoriasis. Patients were followed up to 25 years until the development of the primary outcome of PsA or the censor date. The exposure of interest was the development of MDD. Cox proportional-hazards models showed that patients with psoriasis who developed MDD were at significantly increased risk of subsequently developing PsA compared with patients who did not develop MDD, even after accounting for numerous covariates (hazard ratio 1.37, 95% confidence interval 1.05-1.80, P = 0.021). This result was maintained through numerous sensitivity analyses. These data support the hypothesis that MDD increases the risk of developing PsA among patients with psoriasis, suggesting a need for heightened prevention and management of MDD in patients with psoriasis.

Concepts: Rheumatoid arthritis, Cognitive behavioral therapy, Major depressive disorder, Primary care, Depression, Psoriatic arthritis, Psoriasis, Light therapy

40

Itch is a highly prevalent and multi-dimensional symptom. We aimed to analyze the association between itch and mental health in dermatological patients. This multi-center study is observational cross-sectional conducted in dermatological clinics across 13 European countries. A total of 3530 patients and 1094 healthy controls were included. Patients were examined clinically. Outcome measures were itch (presence, chronicity and intensity), the Hospital Anxiety and Depression Scale, EQ5D-VAS, sociodemographics, suicidal ideation, stress (negative life events and economic difficulties). Ethical approval was obtained. Results showed significant association between the presence of itch in patients and clinical depression, suicidal ideation and economic difficulties (odds ratios respectively OR 1.53 (95% CI 1.15 to 2.02), OR 1.27 (95% CI 1.01 to 1.60), OR 1.24 (95% CI 1.10 to 1.50). The mean score of reported generic health status assessed by the EQ5D-VAS was 65.9 (SD=20.1) in patients with itch, compared to 74.7 (SD= 18.0) in patients without itch, p value < .001 and 74.9 (SD= 15.7) in controls with itch compared to 82.9 (SD= 15.6) in controls without itch, p value <.001. Itch contributes substantially to the psychological disease burden in dermatological patients and the management of patients should include access to multidisciplinary care.

34

Papain is commonly used in food, pharmaceutical, textile and cosmetic industries and is known to induce occupational allergic asthma. We have previously shown that the papain-like cysteine protease Der p 1 from house dust mite per se exhibits percutaneous sensitization potential. We aimed here to investigate the potential of papain itself in epicutaneous sensitization. The effects of papain on tight junction proteins were tested in-vitro in human primary keratinocytes. Using C57BL/6 WT and TLR4-deficient mice, we analyzed the sensitization potential of papain, its effects on the skin barrier and immune cell recruitment. Our results show, that papain affects the skin barrier by increasing transepidermal water loss, degrading tight junction proteins and inducing vasodilation. When topically applied, papain exhibited a high epicutaneous inflammatory potential by recruiting neutrophils, mast cells and CD3-positive cells and by induction of a TH2-biased antibody response. However, its high potency for specific sensitization via the skin was independent of its enzymatic function. The mechanism for specific sensitization was TLR4-independent and, in spite of its capacity to degrade epidermal tight junction proteins, does not rely on its enzymatic function. From our data we conclude that papain has all features to act as a strong allergen via the skin.Journal of Investigative Dermatology accepted article preview online, 23 February 2015. doi:10.1038/jid.2015.58.

Concepts: Immune system, Antibody, Enzyme, Asthma, Immunology, Allergy, Mast cell, House dust mite

31

While the global incidence of cutaneous melanoma is increasing, survival rates for patients with metastatic disease remain less than 10%. Novel treatment strategies are therefore urgently required, particularly for patients bearing BRAF/NRAS wildtype tumours. Targeting autophagy is a novel means to promote cancer cell death in chemotherapy-resistant tumours and the aim of the present study was to test the hypothesis that cannabinoids promote autophagy-dependent apoptosis in melanoma. Treatment with Δ(9)-Tetrahydrocannabinol (THC) resulted in the activation of autophagy, loss of cell viability and activation of apoptosis, while co-treatment with chloroquine or knockdown of Atg7, but not Beclin-1 or Ambra1, prevented THC-induced autophagy and cell death in vitro. Administration of Sativex-like (a laboratory preparation comprising equal amounts of THC and cannabidiol (CBD)) to mice bearing BRAF wildtype melanoma xenografts substantially inhibited melanoma viability, proliferation and tumour growth paralleled by an increase in autophagy and apoptosis compared to standard single agent temozolomide. Collectively our findings suggest THC activates non-canonical autophagy-mediated apoptosis of melanoma cells, suggesting cytotoxic autophagy induction with Sativex warrants clinical evaluation for metastatic disease.Journal of Investigative Dermatology accepted article preview online, 10 February 2015. doi:10.1038/jid.2015.45.

Concepts: Cancer, Breast cancer, Metastasis, Oncology, Lung cancer, Chemotherapy, Melanoma, Cannabidiol

30

We previously reported modest clinical 3-year benefit for topical imiquimod compared with surgery for superficial or nodular basal cell carcinoma at low-risk sites in our noninferiority randomized controlled SINS trial. Here we report 5-year data. Participants were randomized to imiquimod 5% cream once daily (superficial basal cell carcinoma, 6 weeks; nodular basal cell carcinoma, 12 weeks) or excisional surgery (4-mm margin). The primary outcome was clinical absence of initial failure or signs of recurrence at the 3-year dermatology review. Five-year success was defined as 3-year success plus absence of recurrences identified through hospital, histopathology, and general practitioner records. Of 501 participants randomized, 401 contributed to the modified intention-to-treat analyses at year 3 (primary outcome), 383 (96%) of whom had data at year 5. Five-year success rates for imiquimod were 82.5% (170/206) compared with 97.7% (173/177) for surgery (relative risk of imiquimod success = 0.84, 95% confidence interval = 0.77-0.91, P < 0.001). These were comparable to year 3 success rates of 83.6% (178/213) and 98.4% (185/188) for imiquimod and surgery, respectively. Most imiquimod treatment failures occurred in year 1. Although surgery is clearly superior to imiquimod, this study shows sustained benefit for lesions that respond early to topical imiquimod.

Concepts: Cohort study, Clinical trial, Medical statistics, Anatomical pathology, Squamous cell carcinoma, Failure, Basal cell carcinoma, Epidermal nevi, neoplasms, cysts