Journal Of Investigative Dermatology

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A Role for the E3 Ubiquitin Ligase NEDD4 in Keloid Pathogenesis

Wed, 2018-11-21 00:00
The molecular pathomechanisms that drive keloid formation are only partially understood. Genetic studies have provided evidence for a genetic predisposition to keloid formation, and a keloid risk allele has been reported in the gene locus for the E3 ubiquitin ligase NEDD4. Fujita et al. (2018) explore the consequences of this genetic risk allele in NEDD4 for inflammation in the skin and for keloid pathogenesis. This study implicates a specific transcript variant of NEDD4, NEDD4-TV3, as a regulator of NF-κB/STAT3–mediated inflammation and provides evidence that an increase in NEDD4-TV3 promotes keloid formation.

Dietary Pyrophosphate Modulates Calcification in a Mouse Model of Pseudoxanthoma Elasticum: Implication for Treatment of Patients

Tue, 2018-11-20 00:00
Pseudoxanthoma elasticum (PXE) is a heritable disease caused by ABCC6 deficiency. Patients develop ectopic calcification in skin, eyes and vascular tissues. ABCC6, primarily found in liver and kidneys, mediates the cellular efflux of ATP, which is rapidly converted into pyrophosphate (PPi), a potent inhibitor of calcification. PXE patients and Abcc6-/- mice display reduced PPi levels in plasma and peripheral tissues. PXE is currently incurable, although some palliative treatments exist. In recent years, we have successfully developed therapeutic methodologies to compensate the PPi deficit in animal models and humans.

Skin-Derived SPINK9 Kills Escherichia coli

Tue, 2018-11-20 00:00
Antimicrobial peptides (AMP) play a critical role in the barrier function of human skin. They offer a fast response to invading microorganisms and hence protect from external microbial infection. Here we showed the isolation of the KLK5 inhibitor SPINK9 as a major antibacterial factor from healthy stratum corneum. Totally, six N-terminal SPINK9 variants were identified in the stratum corneum. Whereas all variants exhibited similar inhibition activities against KLK5, only three variants with either lysine or glutamine as their first N-terminal residues were able to kill various Escherichia coli (E.coli) strains but not other bacteria or fungi.

The Biology and Clinical Features of Cutaneous Polyomaviruses

Tue, 2018-11-20 00:00
Human polyomaviruses are double-stand DNA viruses with a conserved genomic structure, yet they present with diverse tissue tropisms and disease presentations. Merkel cell polyomavirus, trichodysplasia spinulosa polyomavirus, human polyomavirus 6 and 7, and Malawi polyomavirus are shed from the skin, and Merkel cell polyomavirus, trichodysplasia spinulosa polyomavirus, human polyomavirus 6 and 7 have been linked to specific skin diseases. We present an update on the genomic and clinical features of these cutaneous polyomaviruses.

Role of Chemokine Receptor CCR4 and Regulatory T Cells in Wound Healing of Diabetic Mice

Mon, 2018-11-19 00:00
Wound healing is a well-coordinated process that involves inflammatory mediators and cellular responses; however, if any disturbances are present during this process, tissue repair is impaired. Chronic wounds are one of the serious long-term complications associated with diabetes mellitus (DM). The chemokine receptor CCR4 and its respective ligands, CCL17 and CCL22, are involved in regulatory T cell (Treg) recruitment and activation in inflamed skin; however, the role of Treg in wounds is still not clear.

The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma

Fri, 2018-11-16 00:00
Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by the prolyl 3- (C-P3H) and prolyl 4- (C-P4H) hydroxylases is essential for normal cell function. Here we have investigated the expression, transcriptional regulation and function of the C-P3H and C-P4H families in melanoma. We show that the CP3H family exemplified by Leprel1 and Leprel2 are subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumour suppressor function.

Realistic Exposure Study Assists Risk Assessments of ZnO Nanoparticle Sunscreens and Allays Safety Concerns

Thu, 2018-11-15 00:00
The findings of a new study by Mohammed et al. show that after repeated hourly or daily topical applications typically used for sunscreens, zinc oxide nanoparticles do not penetrate into the viable epidermis or cause toxicity in human skin. This important study confirms that the known benefits of using zinc oxide nanoparticles in sunscreen clearly outweigh the perceived risks of using nanosunscreens.

Support for the Safe Use of Zinc Oxide Nanoparticle Sunscreens: Lack of Skin Penetration or Cellular Toxicity after Repeated Application in Volunteers

Thu, 2018-11-15 00:00
Zinc oxide is a widely used broad-spectrum sunscreen, but concerns have been raised about the safety of its nanoparticle (NP) form. We studied the safety of repeated application of agglomerated zinc oxide (ZnO) NPs applied to human volunteers over 5 days by assessing the skin penetration of intact ZnO-NPs and zinc ions and measuring local skin toxicity. Multiphoton tomography with fluorescence lifetime imaging microscopy was used to directly visualize ZnO-NP skin penetration and viable epidermal metabolic changes in human volunteers.

LPA induces keratinocyte differentiation and promotes skin barrier function through the LPAR1/LPAR5-RHO-ROCK-SRF axis

Wed, 2018-11-14 00:00
The skin barrier protects our body from water loss, allergens and pathogens. Profilaggrin (proFLG) is produced by differentiated keratinocytes and is processed into FLG monomers. These monomers crosslink keratin filaments and are also decomposed to natural moisturizing factors in the stratum corneum for skin hydration and barrier function. Deficits in FLG expression impair skin barrier function and underlie skin diseases such as dry skin and atopic dermatitis (AD). However, intrinsic factors that regulate FLG expression and their mechanism of action remain unknown.

The Molecular Basis of Chemical Chaperone Therapy for Oculocutaneous Albinism Type 1A

Wed, 2018-11-14 00:00
Oculocutaneous albinism (OCA) is an autosomal recessive disease characterized by the reduction or complete lack of melanin pigment in the skin, hair and eyes. No effective treatment for OCA is available at present. OCA type 1 (OCA1) is caused by mutations that disrupt the function of tyrosinase (TYR), the rate-limiting enzyme of melanin synthesis. Recently, it was shown that tyrosinase in some OCA1 mutants is retained within the endoplasmic reticulum (ER) and its catalytic activity is lost, a phenomenon known as ER-retention.

Biological effects of IL-26 on T cell-mediated skin inflammation including psoriasis

Sat, 2018-11-10 00:00
Psoriasis is a chronic inflammatory skin disease mainly characterized by epidermal hyperplasia, scaling and erythema, with Th17 cells having a role in its pathogenesis. Although IL-26, known as a Th17 cytokine, is upregulated in psoriatic skin lesions, its precise role is unclear. We now investigate the role of IL-26 in the imiquimod (IMQ)-induced psoriasis-like murine model using human IL-26 transgenic (hIL-26Tg) mice. Erythema symptoms induced by daily applications of IMQ dramatically increased in hIL-26Tg mice as compared with controls.

Risk of second primary cancer in survivors of in situ melanoma

Sat, 2018-11-10 00:00
Invasive melanoma survivors have an increased risk of developing second primary cancers, however, similar risks associated with in situ melanoma haven’t been established.We evaluated 43,829 first primary in situ melanoma survivors diagnosed from 1982-2012 in Queensland, Australia. Risk of second non-melanoma primary cancers was estimated from standardized incidence ratios with 95% confidence intervals.A total of 4,917 (11.3%) in situ melanoma survivors developed a second primary cancer. No net increased risk compared with the general population was found.

Resident memory and recirculating memory T cells cooperate to maintain disease in a mouse model of vitiligo

Sat, 2018-11-10 00:00
Tissue resident memory T cells (Trm) form in the skin in vitiligo and persist to maintain disease, as white spots often recur rapidly after discontinuing therapy. We and others have recently described melanocyte-specific autoreactive Trm in vitiligo lesions. Here, we characterize the functional relationship between Trm and recirculating memory T cells (Tcm) in our vitiligo mouse model. We found that both Trm and Tcm sensed autoantigen in the skin long after stabilization of disease, producing IFNγ, CXCL9, and CXCL10.

Smad7 ameliorates TGFβ-mediated skin inflammation and associated wound healing defects but not the susceptibility to experimental skin carcinogenesis

Sat, 2018-11-10 00:00
We assessed roles of Smad7 in skin inflammation and wound healing using genetic and pharmacological approaches. In K5.TGFβ1/K5.Smad7 bigenic (double transgenic) mice, Smad7 transgene expression reversed TGFβ1 transgene-induced inflammation, fibrosis and subsequent epidermal hyperplasia, and molecularly abolished TGFβ and NF-κB activation. Next, we produced recombinant human Smad7 protein with a Tat-tag (Tat-Smad7) that rapidly enters cells. Subcutaneous injection of Tat-Smad7 attenuated infiltration of F4/80+ and CD11b+ leukocytes and αSMA+ fibroblasts prior to attenuating epidermal hyperplasia in K5.TGFβ1 skin.

Racial/ethnic differences in incidence and persistence of childhood atopic dermatitis

Thu, 2018-11-08 00:00
Although previous studies have explored racial/ethnic differences in incident atopic dermatitis (AD) in childhood, few studies have examined risk factors associated with AD persistence. As such, we sought to examine differences in incidence and persistence of childhood AD by race/ethnicity accounting for socio-demographic characteristics and perinatal vitamin D levels. Using data from Project Viva, a prospective pre-birth cohort in eastern Massachusetts, we studied 1,437 mother-child pairs with known AD status to examine the associations of race/ethnicity with maternally-reported child AD.

Are bacteria infectious pathogens in hidradenitis suppurativa (HS)? Debate at the Symposium for Hidradenitis Suppurativa Advances meeting (November 2017)

Thu, 2018-11-08 00:00
In November 2017, a formal debate on the role of bacteria in the pathogenesis of hidradenitis suppurativa (HS) was held at the 2nd Symposium on Hidradenitis Suppurativa Advances (SHSA) in Detroit, MI. In this report, we present both sides of the argument as debated at the SHSA meeting, and then discuss the potential role of bacteria as classic infectious pathogens versus an alternative pathogenic role as activators of dysregulated commensal bacterial-host interactions. While there was consensus that bacteria play a role in pathogenesis, and thus are pathogenic, there was a compelling discussion about whether bacteria in HS incite an infectious disease as we classically understand it, or whether bacteria might play a different role in HS pathogenesis.