title: Impaired NLRP3 inflammasome expression and function in atopic dermatitis due to Th2 milieu.
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.
  
  
  CONCLUSIONS
  Impaired NLRP3 expression and function may partially explain how skin colonization and infection with S. aureus can contribute to chronic skin inflammation in AD.
authors.affiliation: Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Niebuhr
authors.forename: K
authors.initials: K
authors.lastname: Baumert
authors.forename: A
authors.initials: A
authors.lastname: Heratizadeh
authors.forename: I
authors.initials: I
authors.lastname: Satzger
authors.forename: T
authors.initials: T
authors.lastname: Werfel
mesh_terms: D001427:Bacterial Toxins / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D006460:Hemolysin Proteins / Q000494:pharmacology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011565:Psoriasis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D002352:Carrier Proteins; D016207:Cytokines; D006460:Hemolysin Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C021091:staphylococcal alpha-toxin; D020170:Caspase 1
keywords: NLRP3; atopic dermatitis; lipoteichoic acid; psoriasis; α-toxin