Dataset Information
Filaggrin-dependent secretion of sphingomyelinase protects against staphylococcal ?-toxin-induced keratinocyte death.
Ontology highlight
ABSTRACT: Background
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 ?-toxin. It is unknown whether lack of keratinocyte differentiation predisposes to enhanced lethality from staphylococcal toxins.Objective
We investigated whether keratinocyte differentiation and filaggrin expression protect against cell death induced by staphylococcal ?-toxin.Methods
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. ?-Toxin heptamer formation and acid sphingomyelinase expression were determined by means of immunoblotting.Results
We found that filaggrin expression, occurring as the result of keratinocyte differentiation, significantly inhibits staphylococcal ?-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 ?-toxin binding sites on the keratinocyte surface. Finally, we determined that sphingomyelinase enzymatic activity directly prevents ?-toxin binding and protects keratinocytes against ?-toxin-induced cytotoxicity.Conclusions
The current study introduces the novel concept that S aureus ?-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.
SUBMITTER: Brauweiler AM
PROVIDER: S-EPMC3742335 | biostudies-literature | 2013 Feb
REPOSITORIES: biostudies-literature
Publications
Filaggrin-dependent secretion of sphingomyelinase protects against staphylococcal α-toxin-induced keratinocyte death.
The Journal of allergy and clinical immunology 20121211 2
<h4>Background</h4>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.<h4>Objective</h4>We investigated whether keratinocyte differentiation and filagg ...[more]
