RESUMEN
Staphylococcus epidermidis is an abundant skin commensal capable of activating cutaneous defense responses, such as induction of cytokines and antimicrobial peptides. To permanently colonize human skin and prevent inflammation S. epidermidis needs to control the induction of host defense mediators. We report here that S. epidermidis induces expression of the host regulator protein A20 in human keratinocytes, thereby controlling expression and release of interleukin-1 beta. siRNA-mediated knockdown of A20 expression strongly enhanced the induction of interleukin-1 beta gene expression and protein release in keratinocytes stimulated with S. epidermidis. Furthermore, siRNA-mediated knockdown of A20 resulted in enhanced gene expression and secretion of the antimicrobial peptide human beta-defensin-2 in keratinocytes facing S. epidermidis. Mechanistically, A20 negatively controlled S. epidermidis-induced activation of the transcription factor NF-kappaB. Together, these data indicate that S. epidermidis exploits A20 to attenuate cutaneous defense responses, which may help S. epidermidis to persist on human skin.
Asunto(s)
Interleucina-1beta/metabolismo , Queratinocitos/microbiología , Piel/microbiología , Infecciones Cutáneas Estafilocócicas/microbiología , Staphylococcus epidermidis/patogenicidad , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , beta-Defensinas/metabolismo , Células Cultivadas , Interacciones Huésped-Patógeno , Humanos , Interleucina-1beta/genética , Queratinocitos/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Piel/metabolismo , Infecciones Cutáneas Estafilocócicas/genética , Infecciones Cutáneas Estafilocócicas/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Regulación hacia Arriba , beta-Defensinas/genéticaRESUMEN
BACKGROUND: Genomic approaches have revealed characteristic site specificities of skin bacterial community structures. In addition, in children with atopic dermatitis (AD), characteristic shifts were described at creases and, in particular, during flares, which have been postulated to mirror disturbed skin barrier function, cutaneous inflammation, or both. OBJECTIVE: We sought to comprehensively analyze microbial configurations in patients with AD across body sites and to explore the effect of distinct abnormalities of epidermal barrier function. METHODS: The skin microbiome was determined by using bacterial 16S rRNA sequencing at 4 nonlesional body sites, as well as acute and chronic lesions of 10 patients with AD and 10 healthy control subjects matched for age, sex, and filaggrin (FLG) mutation status. Nonlesional sampling sites were characterized for skin physiology parameters, including chromatography-based lipid profiling. RESULTS: Epidermal lipid composition, in particular levels of long-chain unsaturated free fatty acids, strongly correlated with bacterial composition, in particular Propionibacteria and Corynebacteria abundance. AD displayed a distinct community structure, with increased abundance and altered composition of staphylococcal species across body sites, the strongest loss of diversity and increase in Staphylococcus aureus seen on chronic lesions, and a progressive shift from nonlesional skin to acute and chronic lesions. FLG-deficient skin showed a distinct microbiome composition resembling in part the AD-related pattern. CONCLUSION: Epidermal barrier integrity and function affect the skin microbiome composition. AD shows an altered microbial configuration across diverse body sites, which is most pronounced at sites of predilection and AD. Eczematous affection appears to be a more important determinant than body site.
