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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

78

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

75

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

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

32

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

32

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

28

Macrophages are the main components of inflammation during skin wound healing. They are critical in wound closure and in excessive inflammation, resulting in defective healing observed in chronic wounds. Given the heterogeneity of macrophage phenotypes and functions, we here hypothesized that different subpopulations of macrophages would have different and sometimes opposing effects on wound healing. Using multimarker flow cytometry and RNA expression array analyses on macrophage subpopulations from wound granulation tissue, we identified a Ly6c(lo)MHCII(hi) “noninflammatory” subset that increased both in absolute number and proportion during normal wound healing and was missing in Ob/Ob and MYD88-/- models of delayed healing. We also identified IL17 as the main cytokine distinguishing this population from proinflammatory macrophages and demonstrated that inhibition of IL17 by blocking Ab or in IL17A-/- mice accelerated normal and delayed healing. These findings dissect the complexity of the role and activity of the macrophages during wound inflammation and may contribute to the development of therapeutic approaches to restore healing in chronic wounds.Journal of Investigative Dermatology advance online publication, 13 December 2012; doi:10.1038/jid.2012.368.

Concepts: Immune system, Medicine, Atherosclerosis, Wound healing, Infection, Wound, Chronic wound, Granulation tissue

28

UVB exposure is well known to induce skin photodamage and photoaging that correlates with qualitative and quantitative deterioration of the dermal extracellular matrix (ECM) because of the upregulation of matrix metalloproteinases (MMPs). Although inhibitory effects of tissue inhibitor of metalloproteinases (TIMPs) on most MMPs have been reported, the protective role of TIMP-1 against photodamage is poorly understood. To address this, TIMP-1 function was augmented or abolished in a human skin xenograft photodamage model after the confirmation of significantly diminished TIMP-1 expression both in photoaged and intrinsically aged skins. During a chronic UVB exposure regimen, pre-treatment with a lentiviral vector overexpressing TIMP-1 or concomitant administration of an anti-TIMP-1-neutralizing antibody (NAB) led to photoprotection or more severe photodamage, respectively. Overexpression of TIMP-1 resulted in significant inhibition of UVB-induced ECM degradation, as well as suppression of decreased skin elasticity and roughness, whereas the NAB-mediated inhibition of TIMP-1 had opposite effects. Furthermore, UVB-induced production of the pro-inflammatory cytokine, tumor necrosis factor α, was inhibited by TIMP-1 treatment of human keratinocytes. Taken together, these data shed light on the important role of TIMP-1 in protection and recovery from cutaneous photodamage because of its suppression of ECM degradation and inflammation.

Concepts: Extracellular matrix, Skin, Qualitative research, Tissue, Matrix metalloproteinase, Tumor necrosis factor-alpha, Epidermis, Tissue inhibitor of metalloproteinases

28

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy linked to a contributory virus (Merkel cell polyomavirus). Multiple epidemiologic studies have established an increased incidence of MCC among persons with systemic immune suppression. Several forms of immune suppression are associated with increased MCC incidence, including hematologic malignancies, HIV/AIDS, and immunosuppressive medications for autoimmune disease or transplant. Indeed, immune-suppressed individuals represent ∼10% of MCC patients, a significant overrepresentation relative to the general population. We hypothesized that immune-suppressed patients may have a poorer MCC-specific prognosis and examined a cohort of 471 patients with a combined follow-up of 1,427 years (median 2.1 years). Immune-suppressed patients (n=41) demonstrated reduced MCC-specific survival (40% at 3 years) compared with patients with no known systemic immune suppression (n=430; 74% MCC-specific survival at 3 years). By competing risk regression analysis, immune suppression was a stage-independent predictor of worsened MCC-specific survival (hazard ratio 3.8, P<0.01). Thus, immune-suppressed individuals have both an increased chance of developing MCC and poorer MCC-specific survival. It may be appropriate to follow these higher-risk individuals more closely, and, when clinically feasible, there may be a benefit of diminishing iatrogenic systemic immune suppression.Journal of Investigative Dermatology advance online publication, 29 November 2012; doi:10.1038/jid.2012.388.

Concepts: Immune system, Epidemiology, Cancer, Immunology, Immunosuppressive drug, Merkel cell cancer, Polyomavirus, Merkel cell polyomavirus

27

The time necessary for a treatment to become effective is crucial for patients and physicians but has been largely neglected in the reporting and comparison of clinical trials in dermatology. The aim of this systematic review is to determine the time until the onset of action of systemic agents approved for moderate-to-severe psoriasis. Primary outcome is the time until onset of action (TOA) defined as the weighted mean time until 25% of the patients achieved a PASI 75 response. Among the biologics, infliximab has the shortest TOA (3.5 weeks) followed by ustekinumab (high dose 4.6/low dose 5.1 weeks/not weight adapted), adalimumab (4.6 weeks), etanercept (high dose 6.6/low dose 9.5 weeks) and alefacept (high dose 15.4 weeks/ low dose: no data). Among the conventional treatments, good data is available for CsA (TOA: 6.0 weeks), limited data was found for MTX (TOA: high dose 3.2/low dose 9.9 weeks). No data are available for fumaric acid esters and retinoids. This systematic review provides clinically relevant information on the onset of action of antipsoriatic agents although the data currently available allows only a limited assessment. Psoriasis trials should consider including the time until the onset of action as an additional outcome measure.Journal of Investigative Dermatology accepted article preview online, 20 February 2013; doi:10.1038/jid.2013.78.

Concepts: Rheumatoid arthritis, Infliximab, Psoriatic arthritis, Psoriasis, Etanercept, Immunosuppressants, Adalimumab, Fumaric acid