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• W1977173627 endingPage "427.e2" @default.
• W1977173627 startingPage "421" @default.
• W1977173627 abstract "The skin of patients with atopic dermatitis (AD) has defects in keratinocyte differentiation, particularly in expression of the epidermal barrier protein filaggrin. AD skin lesions are often exacerbated by Staphylococcus aureus-mediated secretion of the virulence factor α-toxin. It is unknown whether lack of keratinocyte differentiation predisposes to enhanced lethality from staphylococcal toxins.We investigated whether keratinocyte differentiation and filaggrin expression protect against cell death induced by staphylococcal α-toxin.Filaggrin-deficient primary keratinocytes were generated through small interfering RNA gene knockdown. RNA expression was determined by using real-time PCR. Cell death was determined by using the lactate dehydrogenase assay. Keratinocyte cell survival in filaggrin-deficient (ft/ft) mouse skin biopsies was determined based on Keratin 5 staining. α-Toxin heptamer formation and acid sphingomyelinase expression were determined by means of immunoblotting.We found that filaggrin expression, occurring as the result of keratinocyte differentiation, significantly inhibits staphylococcal α-toxin-mediated pathogenicity. Furthermore, filaggrin plays a crucial role in protecting cells by mediating the secretion of sphingomyelinase, an enzyme that reduces the number of α-toxin binding sites on the keratinocyte surface. Finally, we determined that sphingomyelinase enzymatic activity directly prevents α-toxin binding and protects keratinocytes against α-toxin-induced cytotoxicity.The current study introduces the novel concept that S aureus α-toxin preferentially targets and destroys filaggrin-deficient keratinocytes. It also provides a mechanism to explain the increased propensity for S aureus-mediated exacerbation of AD skin disease." @default.
• W1977173627 created "2016-06-24" @default.
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• W1977173627 date "2013-02-01" @default.
• W1977173627 modified "2023-09-26" @default.
• W1977173627 title "Filaggrin-dependent secretion of sphingomyelinase protects against staphylococcal α-toxin–induced keratinocyte death" @default.
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• W1977173627 doi "https://doi.org/10.1016/j.jaci.2012.10.030" @default.
• W1977173627 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3742335" @default.
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