filaggrin Dotaz Zobrazit nápovědu
Mutations in the gene encoding for filaggrin (FLG) are major predisposing factors for atopic dermatitis (AD). Besides genetic predisposition, immunological dysregulations considerably contribute to its pathophysiology. For example, thymic stromal lymphopoietin (TSLP) is highly expressed in lesional atopic skin and significantly contributes to the pathogenesis of AD by activating dendritic cells that then initiate downstream effects on, for example, T cells. However, little is known about the direct interplay between TSLP, filaggrin-deficient skin and other immune cells such as T lymphocytes. In the present study, FLG knockdown skin equivalents, characterised by intrinsically high TSLP levels, were exposed to activated CD4+ T cells. T cell exposure resulted in an inflammatory phenotype of the skin equivalents. Furthermore, a distinct shift from a Th1/Th17 to a Th2/Th22 profile was observed following exposure of T cells to filaggrin-deficient skin equivalents. Interestingly, TSLP directly stimulated T cell migration exclusively in filaggrin-deficient skin equivalents even in the absence of dendritic cells, indicating a hitherto unknown role of TSLP in the pathogenesis of AD.
- MeSH
- aktivace lymfocytů MeSH
- buňky Th17 imunologie metabolismus MeSH
- CD4-pozitivní T-lymfocyty imunologie metabolismus MeSH
- cytokiny metabolismus MeSH
- dendritické buňky imunologie metabolismus MeSH
- exprese genu MeSH
- kůže imunologie metabolismus MeSH
- lidé MeSH
- metabolismus lipidů MeSH
- pohyb buněk imunologie MeSH
- proteiny intermediálních filament nedostatek MeSH
- proteiny těsného spoje genetika metabolismus MeSH
- T-lymfocyty - podskupiny imunologie metabolismus MeSH
- Th1 buňky imunologie metabolismus MeSH
- Th2 buňky imunologie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
BACKGROUND: Therapeutic options for atopic dermatitis mostly address the symptoms but causal therapies are still missing. Peroxisome proliferator activated receptor (PPAR) agonists exert beneficial effects in patients suffering this disease, whereas the stimulation of PPARα and γ seemed most promising. OBJECTIVES: To elucidate the effects of the PPARα specific agonist WY14643, the PPARγ agonist ciglitazone, and the dual PPARα+γ agonist docosahexaenoic acid (DHA) on the homeostasis and barrier function of filaggrin deficient skin. METHODS: The effects of the PPAR agonists on skin differentiation were evaluated via qPCR, Western blot, histological or immunofluorescence staining. Skin lipid organization was determined by ATR-FTIR and lipid composition was analyzed by HPTLC. Ultimately, the skin barrier function was assessed by skin absorption studies using the radioactively labeled compound testosterone. RESULTS: Significant upregulation of filaggrin after DHA and WY14643 supplementation, but no effect of ciglitazone, on protein and mRNA level was detected. DHA and WY14643, but not ciglitazone, normalized the molar ratio of the main skin barrier lipids to 1:1:1 (free fatty acids:ceramides:cholesterol). Furthermore, DHA and WY14643 supplementation normalized the skin lipid profile in filaggrin deficient skin, but only WY14643 significantly improved the skin barrier function. CONCLUSION: Supplementation particularly with the PPARα agonist WY14643 improved the homeostasis and barrier function of filaggrin deficient skin models by normalization of the free fatty acid profile underlining the potential of PPAR agonists for the treatment of filaggrin-associated skin diseases.
- MeSH
- časové faktory MeSH
- fenotyp MeSH
- fibroblasty účinky léků metabolismus MeSH
- genotyp MeSH
- kožní absorpce účinky léků MeSH
- kultivované buňky MeSH
- kůže účinky léků metabolismus MeSH
- kyseliny dokosahexaenové farmakologie MeSH
- kyseliny mastné neesterifikované metabolismus MeSH
- lidé MeSH
- membránové proteiny genetika metabolismus MeSH
- metabolismus lipidů účinky léků MeSH
- permeabilita MeSH
- PPAR alfa agonisté metabolismus MeSH
- PPAR gama agonisté metabolismus MeSH
- proteinové prekurzory genetika metabolismus MeSH
- proteiny intermediálních filament nedostatek genetika MeSH
- pyrimidiny farmakologie MeSH
- RNA interference MeSH
- signální transdukce účinky léků MeSH
- testosteron metabolismus MeSH
- thiazolidindiony farmakologie MeSH
- transfekce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Mutations in the filaggrin (FLG) gene are strongly associated with common dermatological disorders such as atopic dermatitis. However, the exact underlying pathomechanism is still ambiguous. Here, we investigated the impact of FLG on skin lipid composition, organization, and skin acidification using a FLG knockdown (FLG-) skin construct. Initially, sodium/hydrogen antiporter (NHE-1) activity was sufficient to maintain the acidic pH (5.5) of the reconstructed skin. At day 7, the FLG degradation products urocanic (UCA) and pyrrolidone-5-carboxylic acid (PCA) were significantly decreased in FLG- constructs, but the skin surface pH was still physiological owing to an upregulation of NHE-1. At day 14, secretory phospholipase A2 (sPLA2) IIA, which converts phospholipids to fatty acids, was significantly more activated in FLG- than in FLG+. Although NHE-1 and sPLA2 were able to compensate the FLG deficiency, maintain the skin surface pH, and ensured ceramide processing (no differences detected), an accumulation of free fatty acids (2-fold increase) led to less ordered intercellular lipid lamellae and higher permeability of the FLG- constructs. The interplay of the UCA/PCA and the sPLA2/NHE-1 acidification pathways of the skin and the impact of FLG insufficiency on skin lipid composition and organization in reconstructed skin are described.
- MeSH
- atopická dermatitida metabolismus patologie MeSH
- fosfolipasy A2, skupina II metabolismus MeSH
- genový knockdown MeSH
- koncentrace vodíkových iontů MeSH
- kůže cytologie metabolismus MeSH
- kyselina pyrrolidonkarboxylová metabolismus MeSH
- kyselina urokanová metabolismus MeSH
- kyseliny mastné neesterifikované metabolismus MeSH
- kyseliny metabolismus MeSH
- lidé MeSH
- metabolismus lipidů fyziologie MeSH
- Na(+)-H(+) antiport metabolismus MeSH
- permeabilita MeSH
- proteiny intermediálních filament nedostatek genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Péče o nejsvrchnější vrstvu kůže je klíčem k udržení stability kožního ekosystému, prevencí vzniku mnohých kožních onemocnění a hraje zásadní roli v léčbě a stabilizaci chronických dermatóz s dysfunkční kožní bariérou, z nichž nejrozšířenější je atopická dermatitida. V ČR je atopický ekzém zjišťován v anamnéze přibližně u 0,8 milionu obyvatel, přibližně 0,6 milionu lidí ve své anamnéze udává asthma bronchiale. Ačkoli je onemocnění geneticky predisponováno, je porucha bariérové funkce kůže jedním z důležitých patogenetických faktorů.
Care of the uppermost layer of the skin is crucial in maintaining the stability of the skin‘s ecosystem, prevents the development of numerous skin diseases, and plays an essential role in the treatment and stabilization of chronic skin conditions with a defective skin barrier function, with atopic dermatitis being the most widely spread. In the Czech Republic, about 0.8 million inhabitants have a history of atopic eczema and approximately 0.6 million people report a history of bronchial asthma. Although there are genetic predispositions to developing the condition, impairment of skin barrier function is among important pathogenetic factors.
- Klíčová slova
- hydrolipidický film, lipidy glandulární, lipidy epidermální, atopický ekzém, filaggrin,
- MeSH
- atopická dermatitida patofyziologie terapie MeSH
- dítě MeSH
- emoliencia terapeutické užití MeSH
- epidermis anatomie a histologie fyziologie patofyziologie MeSH
- fyziologie kůže MeSH
- kůže anatomie a histologie MeSH
- lidé MeSH
- lipidy fyziologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
