Journal Of Investigative Dermatology

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A Hairy Tale of Monocytes and Contact Hypersensitivity Reactions

Fri, 2018-06-01 00:00
Hair follicles have recently emerged as immunologically active organs that orchestrate recruitment and trafficking of immune cells within skin. Liu et al. (2018) expand our knowledge in this growing area of research by characterizing the network of immune cell interactions during experimental contact hypersensitivity that, interestingly, is centered around hair follicles.

Cooling the Itch via TRPM8

Fri, 2018-06-01 00:00
Cooling is an effective temporary remedy for itch, bringing welcome relief to itchy insect bites, nettle stings, poison ivy, atopic dermatitis, and psoriasis. Menthol, causing a cooling sensation, has similar itch-relieving effects. Palkar et al. demonstrate that TRPM8, a menthol- and cold-activated ion channel, is essential for cooling to relieve itch, suggesting that pharmacologic TRPM8 activation should be explored further as an antipruritic strategy.

Research Techniques Made Simple: Mass Spectrometry for Analysis of Proteins in Dermatological Research

Fri, 2018-06-01 00:00
Identifying previously unknown proteins or detecting the presence of known proteins in research samples is critical to many experiments conducted in life sciences, including dermatology. Sensitive protein detection can help elucidate new intervention targets and mechanisms of disease, such as in autoimmune blistering skin diseases, atopic eczema, or other conditions. Historically, peptides from highly purified single proteins were sequenced, with many limitations, by stepwise degradation from the N-terminus to the C-terminus with subsequent identification by UV absorbance spectroscopy of the released amino acids (i.e., Edman degradation).

E3 ligase Trim21 ubiquitylates and stabilizes Keratin 17 to induce STAT3 activation in psoriasis

Thu, 2018-05-31 00:00
Keratin 17 (K17), a marker of keratinocyte hyperproliferation, is a type I intermediate filament which is overexpressed in psoriatic epidermis and plays a critical pathogenic role by stimulating T cells. However, the posttranslational modification of K17, which is reversible and targetable, has not been elucidated. Herein, we reported that K17 could be modified through ubiquitination that controlled its stability and led to the phosphorylation and nuclear translocation of its interactor STAT3, which is a key regulator of cell proliferation in psoriasis.

Differential Roles of Rad18 and Chk2 in Genome Maintenance and Skin Carcinogenesis Following UV Exposure

Thu, 2018-05-31 00:00
Defects in DNA polymerase Eta (Polη) cause the sunlight-sensitivity and skin cancer-propensity disorder xeroderma pigmentosum variant (XP-V). The extent to which Polη function depends on the upstream E3 ubiquitin ligase Rad18 is controversial and has not been investigated using mouse models. Therefore, we tested the role of Rad18 in UV-inducible skin tumorigenesis. Because Rad18-deficiency leads to compensatory DNA damage signaling by Chk2, we also investigated genetic interactions between Rad18 and Chk2 in vivo.

Enhanced Platelet-activating Factor synthesis facilitates acute and delayed effects of ethanol intoxicated thermal burn injury.

Tue, 2018-05-29 00:00
Thermal burn injuries in patients alcohol intoxicated result in greater morbidity and mortality. Murine models combining ethanol and localized thermal burn injury reproduce the systemic toxicity seen in human subjects, which consists of both acute systemic cytokine production with multiple organ dysfunction, as well as a delayed systemic immunosuppression. However, the exact mechanisms for these acute and delayed effects are unclear. These studies sought to define the role of the lipid mediator Platelet-activating factor (PAF) in the acute and delayed effects of intoxicated burn injury.

Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B Cell Lymphoma, Leg Type

Tue, 2018-05-29 00:00
Cutaneous diffuse large B cell lymphomas (DLBCL) are aggressive lymphomas with a poor prognosis. To elucidate their genetic bases, we analyzed exome sequencing of 37 cutaneous DLBCLs including 31 DLBCL-leg type (DLBCL-LT) and 6 cutaneous DLBCL-not otherwise specified (DLBCL-NOS). As reported previously, 77% of DLBCL-LTs harbor NF-κB-activating MYD88 mutations. In nearly all MYD88-wild type DLBCL-LTs, we found cancer-promoting mutations which either activate the NF-κB pathway through alternative genes (NFKBIE or REL) or activate other canonical cancer pathways (BRAF, MED12, PIK3R1, and STAT3).

Melanoma-derived Soluble DC-HIL/GPNMB Promotes Metastasis by Excluding T-lymphocytes from the Pre-metastatic Niches

Tue, 2018-05-29 00:00
Soluble factors from the primary tumor induce recruitment of bone marrow-derived progenitors (BMPs) to form tumor-supportive microenvironments or pre-metastatic niches (PMNs) in distal organs before metastasis. How tumor-secreted factors condition the sites for tumor progression remains ambiguous. B16 melanoma produces the secreted form of T cell-inhibitory DC-HIL (sDC-HIL) that travels to distal organs and potentiates the metastatic capacity of tumor cells. We studied the molecular mechanisms. sDC-HIL binds to select endothelial cells (ECs) that colocalize with the sites where BMPs and tumor cells migrate.

Chitosan-carboxymethyl-5-fluorouracil-folate conjugate particles: Microwave modulated uptake by skin and melanoma cells

Tue, 2018-05-29 00:00
5-Fluorouracil delivery profiles in the form of chitosan-folate submicron particles through skin and melanoma cells in vitro were examined using microwave as the penetration enhancer. Its in vivo pharmacokinetics profiles were also determined. Chitosan-carboxymethyl-5-fluorouracil-folate conjugate was synthesized and processed into submicron particles by spray drying technique. The size, zeta potential, morphology, drug content, drug release, as well as skin permeation and retention, pharmacokinetics, in vitro SKMEL-28 melanoma cell line cytotoxicity and intracellular trafficking profiles of drug/particles were examined, as a function of skin/melanoma cell treatment by microwave at 2450 MHz for 5 + 5 min.

Association study and fine-mapping major histocompatibility complex analysis of pemphigus vulgaris in a Han Chinese population

Tue, 2018-05-29 00:00
To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study (GWAS) of 240 PV cases and 1,031 controls, and we selected the top single nucleotide polymorphisms (SNPs) for replication in independent samples, with 252 cases and 1,852 controls. We identified rs11218708 (P= 3.1 × 10-8, OR=1.54) at 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the MHC region demonstrated three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10-38;OR = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10-12; OR= 3.25), and rs1051336 at the HLA-DRA gene (P= 3.06 × 10-6; OR = 0.33).

The Neuropeptide Y system regulates both mechanical and histaminergic itch

Thu, 2018-05-24 00:00
Itch is a somatosensory modality that serves to alert the organism to harmful elements removable by scratching, such as parasites and chemical irritants. Recently, ablation or silencing of neuropeptide Y (NPY)-expressing spinal interneurons was reported to selectively enhance mechanical itch whereas chemical itch was unaffected. We have examined the effect of activating the NPY/Y1 receptor system on scratch behavior in mouse. We found that intrathecal administration of the Y1 agonist [Leu31,Pro34]-NPY (LP-NPY) attenuated itch behavior induced by application of 0.07 g von Frey filament in the nape of the neck, compared to saline treatment, indicating that activation of the spinal NPY/Y1 system dampens mechanical itch.

Loss of 5-hydroxymethylcytosine is an epigenetic biomarker in cutaneous T cell lymphoma

Thu, 2018-05-24 00:00
DNA hydroxymethylation at the 5 position of cytosine (5-hmC) is a product of the ten-eleven translocation (TET) family of DNA hydroxylases. Accumulating evidence shows that loss of 5-hmC is critical for various biological and pathological processes. However, its level in cutaneous T cell lymphoma remains largely unknown. Here we report that the loss of 5-hmC is an epigenetic hallmark of cutaneous T cell lymphoma (CTCL), with diagnostic and prognostic implications. Immunohistochemistry staining on 90 mycosis fungoides (MF) cases demonstrated a significant decrease of 5-hmC staining in CD4+ T cells in patch and tumor stages, especially in MF-LCT, compared to benign inflammatory dermatoses.

Epidermal HMGB1 activates dermal fibroblasts and causes hypertrophic scar formation in reduced hydration

Sat, 2018-05-19 00:00
High-mobility group box 1 (HMGB1) protein is a multifunctional cytokine involved in inflammatory reactions and is known to play a key role in tissue repair and fibrosis. However, the function of HMGB1 in fibrotic skin diseases, such as hypertrophic scar formation, remains unclear. In this study, HMGB1 was detected in the nuclei of epidermal cells in normal skin and had accumulated in the cytoplasm in hypertrophic scars. By establishing a keratinocyte-fibroblast co-culture and conditional medium treatment models, we found that a reduced hydration condition increased the expression and secretion of HMGB1 in keratinocytes, subsequently activating dermal fibroblasts.

Vitamin D receptor is required for proliferation, migration and differentiation of epidermal stem cells and progeny during cutaneous wound repair

Sat, 2018-05-19 00:00
Epidermal stem cells residing in the skin play an essential role in epidermal regeneration. When skin is injured, the stem cells are first activated to proliferate, and subsequently the progeny migrate and differentiate to regenerate the epidermis. Here, we demonstrate that the vitamin D receptor (VDR) is essential for these processes to occur. The requirement for VDR on epidermal stem cell function was revealed in conditional VDR knockout (cKO) mice, in which VDR was deleted from stem cells and progeny, and mice were maintained on a low calcium diet.

MCV-miR-M1 targets the host-cell immune response resulting in the attenuation of neutrophil chemotaxis

Thu, 2018-05-17 00:00
Virus-encoded miRNAs are emerging as key regulators of persistent infection and host-cell immune evasion. Merkel cell polyomavirus (MCPyV), the predominant aetiological agent of Merkel cell carcinoma (MCC), encodes a single miRNA, MCV-miR-M1, which targets the oncogenic MCPyV large T antigen (LT). MCV-miR-M1 has previously been shown to play an important role in establishment of long-term infection, however, the underlying mechanism is not fully understood. A key unanswered question is whether, in addition to auto-regulating LT, MCV-miR-M1 also targets cellular transcripts to orchestrate an environment conducive for persistent infection.

Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation

Tue, 2018-05-15 00:00
Formation of scars following wounding or trauma represents a significant healthcare burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model. Clinical translation of FAKI therapy has been challenging, however, due to the lack of an effective drug delivery system for extensive burn injuries, blast injuries, and large excisional injuries.

Filaggrin 2 deficiency results in abnormal cell-cell adhesion in the cornified cell layers and causes peeling skin syndrome type A

Fri, 2018-05-11 00:00
Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial detachment of the epidermal cornified cell layers, often associated with inflammatory features. Here we report on a consanguineous family featuring non-inflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which co-segregated with the disease phenotype in the family.