Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling

Glycerol is used in many skin care products because it improves skin function. Anecdotal reports by patients on the National Psoriasis Foundation website also suggest that glycerol may be helpful for the treatment of psoriasis, although to date no experimental data confirm this idea. Glycerol entry into epidermal keratinocytes is facilitated by aquaglyceroporins like aquaporin-3 (AQP3), and its conversion to phosphatidylglycerol, a lipid messenger that promotes keratinocyte differentiation, requires the lipid-metabolizing enzyme phospholipase-D2 (PLD2). To evaluate whether glycerol inhibits inflammation and psoriasiform lesion development in the imiquimod (IMQ)-induced mouse model of psoriasis, glycerol’s effect on psoriasiform skin lesions was determined in IMQ-treated wild-type and PLD2 knockout mice, with glycerol provided either in drinking water or applied topically. Psoriasis area and severity index, ear thickness and ear biopsy weight, epidermal thickness, and inflammatory markers were quantified. Topical and oral glycerol ameliorated psoriasiform lesion development in wild-type mice. Topical glycerol appeared to act as an emollient to induce beneficial effects, since even in PLD2 knockout mice topical glycerol application improved skin lesions. In contrast, the beneficial effects of oral glycerol required PLD2, with no improvement in psoriasiform lesions observed in PLD2 knockout mice. Our findings suggest that the ability of oral glycerol to improve psoriasiform lesions requires its PLD2-mediated conversion to phosphatidylglycerol, consistent with our previous report that phosphatidylglycerol itself improves psoriasiform lesions in this model. Our data also support anecdotal evidence that glycerol can ameliorate psoriasis symptoms and therefore might be a useful therapy alone or in conjunction with other treatments.

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Regulatory Mechanism for Exfoliative Toxin Production inStaphylococcus aureus

Infection and Immunity ◽

10.1128/iai.00872-10 ◽

2011 ◽

Vol 79 (4) ◽

pp. 1660-1670 ◽

Cited By ~ 24

Author(s):

Fuminori Kato ◽

Noriko Kadomoto ◽

Yuko Iwamoto ◽

Katsuaki Bunai ◽

Hitoshi Komatsuzawa ◽

...

Keyword(s):

Mouse Model ◽

Regulatory Mechanism ◽

Toxin Production ◽

Neonatal Mouse ◽

Epidermal Keratinocytes ◽

Global Regulators ◽

Exfoliative Toxin ◽

Blistering Disease

ABSTRACTThe exfoliative toxin (ET) is a major virulence factor ofStaphylococcus aureusthat causes bullous impetigo and its disseminated form, staphylococcal scalded-skin syndrome (SSSS). ET selectively digests one of the intracellular adhesion molecules, desmoglein 1, of epidermal keratinocytes and causes blisters due to intraepidermal cell-cell dissociation. MostS. aureusstrains that cause blistering disease produce either ETA or ETB. They are serologically distinct molecules, where ETA is encoded on a phage genome and ETB is enocded on a large plasmid. ETA-producingS. aureusstrains are frequently isolated from impetigo patients, and ETB-producingS. aureusstrains are isolated from SSSS. ET-induced blister formation can be reproduced with the neonatal mouse. To determine the regulatory mechanism of ET production, we investigated the role of the two-component systems and global regulators foretaoretbexpressionin vitroandin vivowith the mouse model. Western blot and transcription analyses using a series of mutants demonstrate ETA production was downregulated bysigB,sarS, andsarA, while ETB production was downregulated bysigBandsarAbut not bysarS. Production of both toxins is upregulated bysaeRS,arlRS, andagrCA. Furthermore, by thein vivoneonatal mouse model,sigBandsarSbut notsarAnegatively regulate the exfoliation activity of the ETA-producing strain, whilesarAnegatively regulates the ETB-producing strain. In both strains,saeRS,arlRS, andagrCApositively regulate the exfoliation activityin vivo. The data illustrate similar but distinct regulatory mechanisms for ETA and ETB productionin S. aureus in vitroas well asin vivo.

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Indirubin attenuates mouse psoriasis-like skin lesion in a CD274-dependent manner: an achievement of RNA sequencing

Bioscience Reports ◽

10.1042/bsr20180958 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 2

Author(s):

Xiaochun Xue ◽

Jianhua Wu ◽

Junhui Li ◽

Jianguo Xu ◽

Haiying Dai ◽

...

Keyword(s):

Network Analysis ◽

Skin Lesion ◽

Candidate Genes ◽

Rna Sequencing ◽

Molecular Mechanisms ◽

Regulatory Mechanisms ◽

Epidermal Keratinocytes ◽

Dependent Manner ◽

Human Epidermal Keratinocytes ◽

Ifn Γ

It was previously reported that the expression of CD274 was down-regulated in psoriatic epidermis, leading to immune disorders of psoriasis. However, the regulatory mechanisms of CD274 were rarely elucidated. We aimed to explore the regulatory mechanisms of CD274. Skin samples were collected from 18 patients with psoriasis vulgaris and 9 healthy participants for RNA sequencing. Candidate genes were chosen based on degree and k-core difference of genes in the co-expression network. The relations between candidate genes and CD274 were validated by flow cytometry and real-time PCR in primary human epidermal keratinocytes. The therapeutic effect of indirubin was assessed in an imiquimod-treated mouse model. Interferon-γ (IFN-γ), cyclin-dependent kinase (CDK) 1, Toll-like receptor 3 (TLR3), TLR4 and interleukin (IL)-17A were considered as candidate genes. In primary human epidermal keratinocytes, the level of CD274 was obviously increased under the stimulation of IFN-γ and CDK1 inhibitor (indirubin), independent of TLR4, TLR3 or IL-17A. Indirubin alleviated the severity of psoriatic mice in a CD274-dependent manner. Co-expression network analysis served as an effective method for the exploration of molecular mechanisms. We demonstrated for the first time that CD274 was the regulator of indirubin-mediated effect on mouse psoriasis-like skin lesion based on co-expression network analysis, contributing to the alleviation of mouse psoriasis-like skin lesion.

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Daphnetin inhibits proliferation and inflammatory response in human HaCaT keratinocytes and ameliorates imiquimod-induced psoriasis-like skin lesion in mice

Biological Research ◽

10.1186/s40659-020-00316-0 ◽

2020 ◽

Vol 53 (1) ◽

Author(s):

Jintao Gao ◽

Fangru Chen ◽

Huanan Fang ◽

Jing Mi ◽

Qi Qi ◽

...

Keyword(s):

Skin Lesion ◽

Inflammatory Response ◽

Mouse Model ◽

Nuclear Translocation ◽

Marker Gene ◽

Inflammatory Factors ◽

Mrna Levels ◽

Hacat Keratinocytes ◽

Tnf Α

Abstract Background Psoriasis is a common chronic inflammatory skin disease. Keratinocytes hyperproliferation and excessive inflammatory response contribute to psoriasis pathogenesis. The agents able to attenuate keratinocytes hyperproliferation and excessive inflammatory response are considered to be potentially useful for psoriasis treatment. Daphnetin exhibits broad bioactivities including anti-proliferation and anti-inflammatory. This study aims to evaluate the anti-psoriatic potential of daphnetin in vitro and in vivo, and explore underlying mechanisms. Methods HaCaT keratinocytes was stimulated with the mixture of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α (M5) to establish psoriatic keratinocyte model in vitro. Cell viability was measured using Cell Counting Kit-8 (CCK-8). Quantitative Real-Time PCR (qRT-PCR) was performed to measure the mRNA levels of hyperproliferative marker gene keratin 6 (KRT6), differentiation marker gene keratin 1 (KRT1) and inflammatory factors IL-1β, IL-6, IL-8, TNF-α, IL-23A and MCP-1. Western blotting was used to detect the protein levels of p65 and p-p65. Indirect immunofluorescence assay (IFA) was carried out to detect p65 nuclear translocation. Imiquimod (IMQ) was used to construct psoriasis-like mouse model. Psoriasis severity (erythema, scaling) was scored based on Psoriasis Area Severity Index (PASI). Hematoxylin and eosin (H&E) staining was performed to examine histological change in skin lesion. The expression of inflammatory factors including IL-6, TNF-α, IL-23A and IL-17A in skin lesion was measured by qRT-PCR. Results Daphnetin attenuated M5-induced hyperproliferation in HaCaT keratinocytes. M5 stimulation significantly upregulated mRNA levels of IL-1β, IL-6, IL-8, TNF-α, IL-23A and MCP-1. However, daphnetin treatment partially attenuated the upregulation of those inflammatory cytokines. Daphnetin was found to be able to inhibit p65 phosphorylation and nuclear translocation in HaCaT keratinocytes. In addition, daphnetin significantly ameliorate the severity of skin lesion (erythema, scaling and epidermal thickness, inflammatory cell infiltration) in IMQ-induced psoriasis-like mouse model. Daphnetin treatment attenuated IMQ-induced upregulation of inflammatory cytokines including IL-6, IL-23A and IL-17A in skin lesion of mice. Conclusions Daphnetin was able to attenuate proliferation and inflammatory response induced by M5 in HaCaT keratinocytes through suppression of NF-κB signaling pathway. Daphnetin could ameliorate the severity of skin lesion and improve inflammation status in IMQ-induced psoriasis-like mouse model. Daphnetin could be an attractive candidate for future development as an anti-psoriatic agent.

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Elevated transglutaminase-2 expression in the epidermis of psoriatic skin and its role in the skin lesion development

The Journal of Dermatology ◽

10.1111/1346-8138.13742 ◽

2017 ◽

Vol 44 (6) ◽

pp. 699-702 ◽

Cited By ~ 2

Author(s):

Ching-Chyuan Su ◽

Tzu-Rong Su ◽

Ji-Ching Lai ◽

Gregory-J Tsay ◽

Hung-Ke Lin

Keyword(s):

Skin Lesion ◽

Transglutaminase 2 ◽

Psoriatic Skin ◽

Lesion Development

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Rate ofLeishmania-induced skin-lesion development in rodents depends on the site of inoculation

Parasitology ◽

10.1017/s0031182000055803 ◽

1987 ◽

Vol 94 (3) ◽

pp. 451-465 ◽

Cited By ~ 20

Author(s):

C. E. Kirkpatrick ◽

T. J. Nolan ◽

J. P. Farrell

Keyword(s):

Skin Lesion ◽

Skin Temperature ◽

Metastatic Disease ◽

Regional Differences ◽

The Body ◽

Lesion Development ◽

Golden Hamsters ◽

Immunological Reactions ◽

Different Strains

Regional differences in the response of mice to infection with three strains of dermotropicLeishmaniaspp. were shown for skin covering the trunk. Lesions tended to appear earlier and to grow more rapidly on sites over the caudal half of the body than the cranial half, and caudal lesions were more likely than cranial ones to result in metastatic disease in susceptible strains of mice. Site-related variations in lesion development were observed in different strains of mice as well as in golden hamsters. The effect of these regional differences on the development of some parasite-specific, immunological reactions was examined, as were parasite thermosensitivity and location-related variations in host skin temperature as possible explanations.

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