M Niebuhr1, K Baumert, A Heratizadeh, I Satzger, T Werfel. 1. Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
Abstract
BACKGROUND: Atopic dermatitis (AD) and psoriasis patients are frequently colonized with Staphylococcus aureus (S. aureus) that produce the staphylococcal exotoxin α-toxin. However, only patients with AD suffer from bacterial superinfections with this pathogen, which implicates immunological differences in AD vs psoriasis in combating these bacteria. S. aureus recognition is partially mediated by intracellular nucleotide-binding oligomerization domain receptors (NLRs), which link α-toxin to caspase-1 activation through the formation of the NLRP3 inflammasome and to IL-1β secretion. OBJECTIVE: To investigate (i) NLRP3 expression in the context of different T-helper cytokine milieus and (ii) its function in response to sublytic α-toxin stimulation in patients with AD and psoriasis compared with healthy controls. METHODS: NLRP3 expression and function were investigated in lesional AD and psoriasis skin as well as in primary keratinocytes (HPKs) and monocytes upon stimulation with Th1, Th2, Th17 and Th22 cytokines or staphylococcal α-toxin, respectively, at the mRNA and protein (ELISA, immunohistochemistry and immunofluorescence) level. RESULTS: NLRP3 and caspase-1 expressions were reduced in lesional AD skin compared to psoriatic and healthy skin. IL-4, IL-5 and IL-13 downregulated NLRP3 and ASC, whereas interferon-γ upregulated NLRP3 in HPKs. In monocytes, caspase-1 expression was reduced by Th2 cytokines and enhanced by a Th1 milieu. Caspase-1-dependent IL-1β secretion was impaired in monocytes from patients with AD compared to patients with psoriasis and healthy controls by α-toxin stimulation following priming with lipoteichoic acid. CONCLUSION: Impaired NLRP3 expression and function may partially explain how skin colonization and infection with S. aureus can contribute to chronic skin inflammation in AD.
BACKGROUND:Atopic dermatitis (AD) and psoriasispatients are frequently colonized with Staphylococcus aureus (S. aureus) that produce the staphylococcal exotoxin α-toxin. However, only patients with AD suffer from bacterial superinfections with this pathogen, which implicates immunological differences in AD vs psoriasis in combating these bacteria. S. aureus recognition is partially mediated by intracellular nucleotide-binding oligomerization domain receptors (NLRs), which link α-toxin to caspase-1 activation through the formation of the NLRP3 inflammasome and to IL-1β secretion. OBJECTIVE: To investigate (i) NLRP3 expression in the context of different T-helper cytokine milieus and (ii) its function in response to sublytic α-toxin stimulation in patients with AD and psoriasis compared with healthy controls. METHODS:NLRP3 expression and function were investigated in lesional AD and psoriasis skin as well as in primary keratinocytes (HPKs) and monocytes upon stimulation with Th1, Th2, Th17 and Th22 cytokines or staphylococcal α-toxin, respectively, at the mRNA and protein (ELISA, immunohistochemistry and immunofluorescence) level. RESULTS:NLRP3 and caspase-1 expressions were reduced in lesional AD skin compared to psoriatic and healthy skin. IL-4, IL-5 and IL-13 downregulated NLRP3 and ASC, whereas interferon-γ upregulated NLRP3 in HPKs. In monocytes, caspase-1 expression was reduced by Th2 cytokines and enhanced by a Th1 milieu. Caspase-1-dependent IL-1β secretion was impaired in monocytes from patients with AD compared to patients with psoriasis and healthy controls by α-toxin stimulation following priming with lipoteichoic acid. CONCLUSION: Impaired NLRP3 expression and function may partially explain how skin colonization and infection with S. aureus can contribute to chronic skin inflammation in AD.
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