scholarly journals LIGHT–HVEM signaling in keratinocytes controls development of dermatitis

2018 ◽  
Vol 215 (2) ◽  
pp. 415-422 ◽  
Author(s):  
Rana Herro ◽  
Jr-Wen Shui ◽  
Sonja Zahner ◽  
Daniel Sidler ◽  
Yuko Kawakami ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Skin Diseases ◽  
Disease Onset ◽  
Epidermal Keratinocytes ◽  
Matricellular Protein ◽  
Central Feature ◽  
Human Epidermal Keratinocytes ◽  
Conditional Deletion ◽  
Tnf Superfamily ◽  
Dermal Collagen

Dermatitis is often associated with an allergic reaction characterized by excessive type 2 responses leading to epidermal acanthosis, hyperkeratosis, and dermal inflammation. Although factors like IL-4, IL-13, and thymic stromal lymphopoietin (TSLP) are thought to be instrumental for the development of this type of skin disorder, other cytokines may be critical. Here, we show that the tumor necrosis factor (TNF) superfamily protein LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes) is required for experimental atopic dermatitis, and LIGHT directly controls keratinocyte hyperplasia, and production of periostin, a matricellular protein that contributes to the clinical features of atopic dermatitis as well as other skin diseases such as scleroderma. Mice with a conditional deletion of the LIGHT receptor HVEM (herpesvirus entry mediator) in keratinocytes phenocopied LIGHT-deficient mice in exhibiting reduced epidermal thickening and dermal collagen deposition in a model of atopic dermatitis driven by house dust mite allergen. LIGHT signaling through HVEM in human epidermal keratinocytes directly induced proliferation and periostin expression, and both keratinocyte-specific deletion of HVEM or antibody blocking of LIGHT–HVEM interactions after disease onset prevented expression of periostin and limited atopic dermatitis symptoms. Developing reagents that neutralize LIGHT–HVEM signaling might be useful for therapeutic intervention in skin diseases where periostin is a central feature.

scholarly journals Autophagy Suppresses Toll-Like Receptor 3-Mediated Inflammatory Reaction in Human Epidermal Keratinocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Xue Mei Li ◽  
Kyung Eun Jung ◽  
Su Hyuk Yim ◽  
Dong Kyun Hong ◽  
Chang Deok Kim ◽  
...  
Keyword(s):  
Inflammatory Reaction ◽  
Skin Diseases ◽  
Poly I:C ◽  
Epidermal Keratinocytes ◽  
Toll Like Receptor ◽  
Inflammatory Skin Diseases ◽  
Human Epidermal Keratinocytes ◽  
Strong Light ◽  
Polycytidylic Acid ◽  
Inflammatory Skin

Autophagy, one mechanism of programmed cell death, is fundamental to cellular homeostasis. Previous studies have identified autophagy as a novel mechanism by which cytokines control the immune response. However, its precise role in immune-related inflammatory skin diseases such as psoriasis remains unclear. Thus, this study explored the functional role of autophagy in psoriatic inflammation of epidermal keratinocytes. Strong light chain 3 immunoreactivity was observed in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model, and it was readily induced by polycytidylic acid (poly (I:C)), which stimulates Toll-like receptor 3 (TLR3), in human epidermal keratinocytes in vitro. Rapamycin-induced activation of autophagy significantly reduced poly (I:C)-induced inflammatory reaction, whereas, inhibition of autophagy by 3-methyladeine increased that. Our results indicate that the induction of autophagy may attenuate TLR3-mediated immune responses in human epidermal keratinocytes, thus providing novel insights into the mechanisms underlying the development of inflammatory skin diseases including psoriasis.

scholarly journals Citrus sudachi Peel Extract Suppresses Cell Proliferation and Promotes the Differentiation of Keratinocytes through Inhibition of the EGFR–ERK Signaling Pathway

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1468
Author(s):  
Shogo Abe ◽  
Misako Ueno ◽  
Mami Nishitani ◽  
Tetsuya Akamatsu ◽  
Takumi Sato ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Egf Receptor ◽  
Skin Diseases ◽  
Receptor Activation ◽  
Inhibitory Effect ◽  
Keratinocyte Differentiation ◽  
Epidermal Keratinocytes ◽  
Human Epidermal Keratinocytes ◽  
Beneficial Effects ◽  
Keratinocyte Cell Line Hacat

Citrus sudachi is a well-known fruit in Tokushima Prefecture, Japan, and its peels are rich in phytochemicals, including phenolic compounds. Although it is expected that the extract of the C. sudachi peel elicits various beneficial physiological activities, the effect on the skin has not been investigated. In this study, we report that the aqueous extract from the peel of C. sudachi suppresses cell proliferation of the immortalized human keratinocyte cell line, HaCaT, and primary normal human epidermal keratinocytes. The extract of C. sudachi peel suppressed epidermal growth factor (EGF)-induced EGF receptor activation and tumor necrosis factor (TNF)-α-induced extracellular regulated kinase (ERK) 1/2 activation, which suggests that the extract exerts its inhibitory effect through inhibition of both the EGF receptor (EGFR) and its downstream molecules. Additionally, the extract of C. sudachi peel potentiated calcium-induced keratinocyte differentiation. These results suggest that the extract of C. sudachi peel may have beneficial effects against skin diseases that are characterized by hyperproliferation of epidermal keratinocytes, such as those seen in psoriasis and in cutaneous squamous cell carcinoma.

scholarly journals Epidermal Growth Factor Relieves Inflammatory Signals inStaphylococcus aureus-Treated Human Epidermal Keratinocytes and Atopic Dermatitis-Like Skin Lesions in Nc/Nga Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Sun Young Choi ◽  
You Jin Lee ◽  
Ji Min Kim ◽  
Hyun Ji Kang ◽  
Sang Hyun Cho ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Opposite Effect ◽  
Egf Receptor ◽  
Skin Lesions ◽  
Epidermal Keratinocytes ◽  
Human Epidermal Keratinocytes ◽  
Epidermal Growth

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a defective immunologic barrier, which is aggravated byStaphylococcus aureus (S. aureus). Epidermal growth factor (EGF) suppresses inflammation and EGF receptor inhibitors increasedS. aureuscolonization. Thus, we investigated the potential roles of EGF in AD, which is often aggravated byS. aureus. We determined how EGF affects the expression of inflammatory cytokines and antimicrobial peptides (AMPs) in human epidermal keratinocytes (HEKs) treated with heat-inactivatedS. aureus(HKSA)in vitroand 2,4-dinitrochlorobenzene-induced AD-like skin lesions in Nc/Nga mice. HKSA increased IL-6 and NFκB expression; EGF treatment had the opposite effect. EGF increased humanβdefensin-2 expression in HEKs and murineβdefensin-3 in mice. In mice, both EGF and pimecrolimus groups showed less erythema with significantly reduced inflammation and decreased expression of thymic stromal lymphopoietin. EGF relievedS. aureus-induced inflammation and AD-like skin lesions in Nc/Nga mice. Therefore, EGF could be a potential topical treatment for AD.

scholarly journals Role of 11β-hydroxysteroid dehydrogenase type 1 in the development of atopic dermatitis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Noo Ri Lee ◽  
Beom Jun Kim ◽  
Chung Hyeok Lee ◽  
Young Bin Lee ◽  
Solam Lee ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
De Novo ◽  
Hydroxysteroid Dehydrogenase ◽  
Whole Body ◽  
Epidermal Keratinocytes ◽  
Human Epidermal Keratinocytes ◽  
Peripheral Tissues

AbstractGlucocorticoids (GCs) are potent anti-inflammatory drugs, the secretion of which is mediated and controlled by the hypothalamic–pituitary–adrenal axis. However, they are also secreted de novo by peripheral tissues for local use. Several tissues express 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), including the skin. The inactive GC cortisone is converted by 11β-HSD1 to active GC cortisol, which is responsible for delayed wound healing during a systemic excess of GC. However, the role of 11β-HSD1 in inflammation is unclear. We assessed whether 11β-HSD1 affects the development of atopic dermatitis (AD) in vitro and in vivo. The expression of 11β-HSD1 in the epidermis of AD lesions was higher than that in the epidermis of healthy controls. Knockdown of 11β-HSD1 in human epidermal keratinocytes increased the production of thymic stromal lymphopoietin. In an oxazolone-induced mouse model of AD, localized inhibition of 11β-HSD1 aggravated the development of AD and increased serum cytokine levels associated with AD. Mice with whole-body knockout (KO) of 11β-HSD1 developed significantly worse AD upon induction by oxazolone. We propose that 11β-HSD1 is a major factor affecting AD pathophysiology via suppression of atopic inflammation due to the modulation of active GC in the skin.

scholarly journals Neurotrophin-4 Production by Human Epidermal Keratinocytes: Increased Expression in Atopic Dermatitis

2000 ◽  
Vol 114 (6) ◽  
pp. 1108-1112 ◽  
Author(s):  
Markus Grewe ◽  
Kathrin Vogelsang ◽  
Thomas Ruzicka ◽  
Helger Stege ◽  
Jean Krutmann
Keyword(s):  
Atopic Dermatitis ◽  
Epidermal Keratinocytes ◽  
Human Epidermal Keratinocytes

scholarly journals Aryl Hydrocarbon Receptor Activation Downregulates IL-33 Expression in Keratinocytes via Ovo-Like 1

2020 ◽  
Vol 9 (3) ◽  
pp. 891 ◽  
Author(s):  
Gaku Tsuji ◽  
Akiko Hashimoto-Hachiya ◽  
Vu Hai Yen ◽  
Sho Miake ◽  
Masaki Takemura ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Aryl Hydrocarbon Receptor ◽  
Crucial Role ◽  
Receptor Activation ◽  
Epidermal Keratinocytes ◽  
Human Epidermal Keratinocytes ◽  
Aryl Hydrocarbon ◽  
Normal Human Epidermal Keratinocytes ◽  
Normal Human ◽  
Susceptible Gene

Background: IL-33, one of the IL-1 superfamily cytokines, has been shown to be associated with pruritus and inflammation in atopic dermatitis (AD). Furthermore, IL-33 production derived from keratinocytes reportedly has a crucial role in the development of AD; however, the mechanism of IL-33 expression has not been fully understood. Methods: We analyzed IL-33 expression in normal human epidermal keratinocytes (NHEKs) treated with IL-4. Results: IL-4 induced the upregulation of IL-33 expression in NHEKs. Based on the findings 1) that ovo-like 1 (OVOL1), a susceptible gene of AD, upregulates filaggrin (FLG) and loricrin (LOR) expression in NHEKs and 2) that reduced expression of FLG and LOR leads to production of IL-1 superfamily cytokines, we examined the involvement of OVOL1 in IL-33 expression in NHEKs. Knockdown of OVOL1 induced upregulation of IL-33 expression. Moreover, because Glyteer, an activator of aryl hydrocarbon receptor (AHR), reportedly upregulates OVOL1 expression, we examined whether treatment with Glyteer inhibited IL-33 expression in NHEKs. Treatment with Glyteer inhibited IL-4-induced upregulation of IL-33 expression, which was canceled by knockdown of either AHR or OVOL1. Conclusions: Activation of the AHR-OVOL1 axis inhibits IL-4-induced IL-33 expression, which could be beneficial for the treatment of AD.

scholarly journals Extract of Scutellaria baicalensis induces semaphorin 3A production in human epidermal keratinocytes

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250663
Author(s):  
Yasuko Yoshioka ◽  
Yayoi Kamata ◽  
Mitsutoshi Tominaga ◽  
Yoshie Umehara ◽  
Ikuyo Yoshida ◽  
...  
Keyword(s):  
Skin Diseases ◽  
Epidermal Keratinocytes ◽  
Dependent Manner ◽  
Semaphorin 3A ◽  
Human Epidermal Keratinocytes ◽  
State Dependent ◽  
Gene Assay ◽  
Normal Human ◽  
Culture Supernatants ◽  
Relative Luciferase Activity

In a disease-state-dependent manner, the histamine-resistant itch in dry skin-based skin diseases such as atopic dermatitis (AD) and xerosis is mainly due to hyperinnervation in the epidermis. Semaphorin 3A (Sema3A) is a nerve repulsion factor expressed in keratinocytes and it suppresses nerve fiber elongation in the epidermis. Our previous studies have shown that Sema3A ointment inhibits epidermal hyperinnervation and scratching behavior and improves dermatitis scores in AD model mice. Therefore, we consider Sema3A as a key therapeutic target for improving histamine-resistant itch in AD and xerosis. This study was designed to screen a library of herbal plant extracts to discover compounds with potential to induce Sema3A in normal human epidermal keratinocytes (NHEKs) using a reporter gene assay, so that positive samples were found. Among the positive samples, only the extract of S. baicalensis was found to consistently increase Sema3A levels in cultured NHEKs in assays using quantitative real-time PCR and ELISA. In evaluation of reconstituted human epidermis models, the level of Sema3A protein in culture supernatants significantly increased by application of the extract of S. baicalensis. In addition, we investigated which components in the extract of S. baicalensis contributed to Sema3A induction and found that baicalin and baicalein markedly increased the relative luciferase activity, and that baicalein had higher induction activity than baicalin. Thus, these findings suggest that S. baicalensis extract and its compounds, baicalin and baicalein, may be promising candidates for improving histamine-resistant itch via the induction of Sema3A expression in epidermal keratinocytes.

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