Journal Of Investigative Dermatology

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Unexpected High Levels of BRN2/POU3F2 Expression in Human Dermal Melanocytic Nevi

Tue, 2019-12-24 00:00
Malignant melanoma (MM) is the most aggressive skin cancer. The majority of cancer associated deaths are due to invasion of cancer cells to distant tissues. It is thus of great importance to understand the mechanisms of metastatic spread. A potential marker for this is BRN2, encoded by the POU3F2 gene, that interacts with SOX transcription factors (Cook and Sturm, 2008, Malik et al., 2018). While some studies consider BRN2 as a positive regulator of MITF, which favours proliferation (Goodall et al., 2004a, Wellbrock et al., 2008), other studies propose a dual function for BRN2 in both tumour proliferation and invasion, which could be controlled via up/down regulation of MITF respectively (Simmons et al., 2017, Wellbrock and Arozarena, 2015).

Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by interferon-mediated barrier disruption

Mon, 2019-12-23 00:00
Cutaneous inflammation is recurrent in systemic lupus erythematosus (SLE), yet mechanisms that drive cutaneous inflammation in SLE are not well-defined. Type I IFNs are elevated in non-lesional SLE skin and promote inflammatory responses. Staphylococcus aureus, known to induce IFN production, could play a role in cutaneous inflammation in SLE. We show here that active cutaneous lupus erythematosus (CLE) lesions are highly colonized (∼50%) by S. aureus. To define the impact of IFNs on S. aureus colonization, we examined the effects of type I and type II IFNs on S.

Inactivation of the cytoprotective major vault protein by caspase-1 and -9 in epithelial cells during apoptosis

Mon, 2019-12-23 00:00
Inflammasome activation induces caspase-1-dependent secretion of the proinflammatory cytokine IL-1β. In addition, caspase-1 activates gasdermin D (GSDMD) in immune cells causing pyroptosis, a lytic type of cell death. In contrast, UVB irradiation of human primary keratinocytes (HPKs) induces NLRP1 inflammasome activation, cytokines secretion and caspase-1-dependent apoptosis, rather than pyroptosis. Here, we addressed the molecular mechanisms underlying the role of caspase-1 in UVB-induced cell death of HPKs.

T-Type calcium channels as potential therapeutic targets in vemurafenib-resistant BRAFV600E melanoma

Mon, 2019-12-23 00:00
Melanoma is a malignant neoplasia that is highly resistant to chemotherapy and radiotherapy and is associated with poor prognosis in advanced stage. Targeting melanoma that harbors the common BRAFV600E mutation with kinase inhibitors, such as vemurafenib, reduces tumor burden, but these tumors frequently acquire resistance to these drugs. We previously proposed that T-type calcium channel (TTCC) expression may serve as a biomarker for melanoma progression and prognosis, and we showed that TTCC blockers reduce migration and invasion rates due to autophagy blockade only in BRAFV600E-mutant melanoma cells.

NKG2D defines a subset of skin effector memory CD8 T cells with pro-inflammatory functions in vitiligo

Mon, 2019-12-23 00:00
Vitiligo is an autoimmune disease that results from the loss of melanocytes, associated with skin infiltration of CD8+ effector memory T (TEM) cells with a Tc1 skewed immune response. Natural killer group 2D (NKG2D) is an activating receptor found on immune cells, in particular NK and activated CD8+ T cells, that is able to produce a high amount of IFN-γ. Here we found that NKG2D expression was increased in vitiligo skin CD8+ TEM cells and was promoted by IL-15. Phenotypic and functional analyses showed that NKG2D+ CD8+ skin TEM cells displayed an activated phenotype and produced elevated levels of both IFN-γ and TNF-α.

Tussilagonone ameliorates psoriatic features in keratinocytes and imiquimod-induced psoriasis-like lesions in mice via Nrf2 activation

Mon, 2019-12-23 00:00
Psoriasis is a common inflammatory skin disorder which is characterized by keratinocyte hyperproliferation and abnormal differentiation, resulting in the thickening of the epidermis and stratum corneum. In the present study, we investigated in vitro and in vivo pharmacological effects of tussilagonone (TGN), a sesquiterpenoid isolated from Tussilago farfara, on transcription factors relevant for the pathogenesis of psoriasis. TGN inhibited activation of NF-kB and STAT3, leading to the attenuated expression of psoriasis-related inflammatory genes and suppression of keratinocytes hyperproliferation.

The Interaction of LILRB2 with HLA-B is Associated with Psoriasis Susceptibility

Sat, 2019-12-21 00:00
The strongest signal for genetic susceptibility to psoriasis resides within the major histocompatibility complex (MHC) near class I loci (Okada et al., 2014). However, the mechanistic basis for how MHC associations confer psoriasis risk has yet to be fully elucidated (Prinz, 2018). Fine-mapping studies have identified specific amino acids in the peptide binding groove of HLA-B and HLA-C as conferring risk (Chen et al., 2012, Okada et al., 2014). This suggests that psoriasis risk may be mediated through HLA presentation of autoantigens.

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

Fri, 2019-12-20 00:00
Although the role of immune dysregulation in hidradenitis suppurativa (HS) has yet to be elucidated, recent studies identified several complement abnormalities in patients with HS. The complement system serves a critical role in the modulation of immune response and regulation of cutaneous commensal bacteria. Complement is implicated in several inflammatory skin diseases including systemic lupus erythematosus, angioedema, pemphigus, bullous pemphigoid, and HS. A model of HS pathogenesis is proposed, integrating the role of commensal bacteria, cutaneous immune responses, and complement dysregulation.

Using Implementation Science to Optimize the Uptake of Evidence-Based Medicine into Dermatology Practice

Thu, 2019-12-19 00:00
An estimated 17-year lag exists between evidence generation and its integration into routine clinical care. The field of implementation science has emerged to close this gap by applying rigorous methods to systematically study the obstacles and facilitators of the uptake of evidence-based practices. However, implementation science has not gained wide traction in dermatology. In this narrative review, we use literature and expert input to introduce implementation science and key frameworks for implementing interventions and evaluating their uptake.

MEETING REPORT: THE 4TH ANNUAL MEETING OF THE CHINESE SOCIETY FOR INVESTIGATIVE DERMATOLOGY

Tue, 2019-12-17 00:00
On October 1, 2019, the Peoples Republic of China celebrated the 70th anniversary of its foundation. The country, from its humble beginnings as an impoverished nation, has experienced over the past 70 years a remarkable economic growth. Accompanying the economic growth, there has been a rapid expansion of the research enterprise in China, including dermatological and cutaneous biology research. This is reflected by the number of English language articles listed in PubMed, which increased over the past decade (2009-2019) from 147 to 1,337, as published by dermatologists in China (Figure 1a).

Staphylococcus aureus skin colonization is enhanced by the interaction of neutrophil extracellular traps with keratinocytes

Tue, 2019-12-17 00:00
Staphylococcus aureus is a facultative pathogen found on skin and nasal surfaces. It is usually absent from the skin of healthy humans but frequently colonizes the skin of atopic dermatitis patients.Here we investigate the functional role of neutrophils in the initial steps of S. aureus skin colonization and how skin commensals modulate the S. aureus-induced recruitment of neutrophils to the skin. By using an epicutaneous mouse skin colonization model we show that skin inflammation induced by tape-stripping leads to a rapid recruitment of neutrophils which correlates with enhanced S.

GNA11 mutation as a cause of Sturge Weber Syndrome - expansion of the phenotypic spectrum of G-protein related mosaicism and the associated clinical diagnoses

Thu, 2019-12-12 00:00
GNA11 and GNAQ are highly homologous genes encoding different Gα subunits of the Gαq subfamily of heterotrimeric G-proteins. GNAQ mutation mosaicism has previously been found to cause Sturge-Weber syndrome (SWS) and isolated capillary malformations(Shirley et al., 2013). We recently described post-zygotic activating mutations in GNA11 or GNAQ as causes of Phakomatosis pigmentovascularis (PPV)(Thomas et al., 2016), a group of conditions defined by the presence of both pigmentary and vascular birthmarks(Happle, 2005, Ota, 1947), and GNAQ mosaicism as a cause of Extensive or atypical dermal melanocytosis (EDM)(Thomas et al., 2016).

Utilizing Machine Learning for Image Quality Assessment for Reflectance Confocal Microscopy

Thu, 2019-12-12 00:00
In vivo reflectance confocal microscopy (RCM) enables clinicians to examine lesions’ morphological and cytological information in epidermal and dermal layers, while reducing the need for biopsies. As RCM is being adopted more widely, the workflow is expanding from real-time diagnosis at the bedside to include a “capture, store and forward” model with image interpretation and diagnosis occurring offsite, similar to radiology. As the patient may no longer be present at the time of image interpretation, quality assurance is key during image acquisition.

Predictive metagenomic analysis reveals a role of cutaneous dysbiosis in the development of hidradenitis suppurativa

Thu, 2019-12-12 00:00
we read with great interest the recent published manuscript by Schneider AM et al.(Schneider et al., 2019). The authors investigated the bacterial microbiome in patients with hidradenitis suppurativa (HS) and healthy controls using Next-Generation Sequencing (NGS) of 16S rRNA marker genes. Overall, the authors demonstrated several factors that point to a potential involvement of the microbiome in the pathogenesis of HS. Indeed, the authors further add to the hypothesis that the reduced presence of sebaceous glands and the subsequent reduced presence of Propionibacteria spp.

Loss of the Epigenetic Mark, 5-hmC, in Psoriasis: Implications for Epidermal Stem Cell Dysregulation

Wed, 2019-12-11 00:00
Epigenetic regulation has profound influence on stem cell fate during normal development in maintenance of physiologic tissue homeostasis. Here we report diminished ten-eleven translocation (TET) methylcytosine dioxygenase expression and loss of the DNA hydroxymethylation mark, 5-hydroxymethylcytosine (5-hmC), in keratinocyte stem cells (KSCs) and transit-amplifying cells (TACs) in human psoriasis and in imiquimod-induced murine psoriasis. Loss of 5-hmC was associated with dysregulated KSC kinetics, resulting in accumulation of nestin and FABP5-expressing TACs to produce classic psoriatic epidermal architecture.

The transcription factor Foxn1 regulates skin adipogenesis and affects susceptibility to diet-induced obesity

Wed, 2019-12-04 00:00
Foxn1, a transcription factor expressed in the epidermis, regulates keratinocyte differentiation and participates in skin wound healing. In the present study, we explored the impact of Foxn1 insufficiency on diet-stimulated weight gain and dermal white adipose tissue regulation in the intact and wounded skin of Foxn1eGFP/+ (heterozygotes, Foxn1 insufficient) mice in the context of age and diet. The results showed that on a high-fat diet, Foxn1eGFP/+ mice gained significantly less body weight than their Foxn1+/+ counterparts (Foxn1-sufficient mice).

Migration and Function of Memory CD8+ T Cells in Skin

Wed, 2019-12-04 00:00
CD8+ memory T cells provide anamnestic host defense against intracellular pathogens and cancer immunosurveillance but are also pathogenic in some autoimmune diseases. In mouse skin, there are two unique subsets of CD8+ memory T cells, resident memory cells that reside long-term in steady state skin and recirculating memory cells that are transient. They have distinct mechanisms of recruitment, development, and maintenance in response to skin-derived signals. In this review, we will focus on these mechanisms and the functional relationship of these two types of CD8+ memory cells with host defense and disease.

Redox Activities of Melanins Investigated by Electrochemical Reverse Engineering: Implications for their Roles in Oxidative Stress

Wed, 2019-12-04 00:00
Melanins, the main epidermal pigments of man, have been viewed traditionally as performing photoprotective and antioxidant functions, yet increasing evidence indicates they also possess detrimental pro-oxidant activities. Understanding this duality in functional activity (anti- vs. pro-oxidant) is important because oxidative stress is believed to play a central role in melanoma pathophysiology. Here, we review current knowledge of melanin’s structure and functional activities and their relevance to redox biology and oxidative stress.

The Utility of T-Cell Clonality in Differential Diagnostics of Acute Graft-vs-Host Disease from Drug Hypersensitivity Reaction

Mon, 2019-12-02 00:00
Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation (HSCT). The skin involvement often appears prior to the involvement of other organs. Cutaneous manifestations of acute GVHD have features that are similar both clinically and histologically to other morbilliform eruptions, such as drug hypersensitivity reaction (DHR) and viral or bacterial exanthem; thus, creating a diagnostic pitfall. The correct diagnosis of DHR vs. GVHD is crucial since the therapy of those two conditions has a different direction: discontinuation of the offending agent in DHR and early administration of a high dose of systemic steroids in GVHD.

BJD Editor's Choice

Sun, 2019-12-01 00:00
This issue of the BJD has a focus on the effect of sunscreen on vitamin D synthesis. The topic remains a contentious issue in the context of skin cancer prevention and high rates of subnormal vitamin D levels in individuals living in temperate climates. Can sunscreen use prevent sunburn while still allowing adequate vitamin D synthesis? The answer from Young et al. is ‘yes’, with appropriate application of a sun protection factor (SPF) 15 sunscreen during a 1-week beach holiday. The new research data are timely given the findings of two reviews considering vitamin D status and sunscreen application that are also published in this issue of the BJD.

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