title: The pattern recognition receptor NOD2 mediates Staphylococcus aureus-induced IL-17C expression in keratinocytes.
abstract: IL-17C is an important epithelial cell-derived cytokine activating innate immunity by the induction of antimicrobial peptides and cytokines. Here, we investigated the role of the cytosolic pattern recognition receptor nucleotide-binding oligomerization domain-containing protein 2 (NOD2) for the Staphylococcus aureus-mediated induction of IL-17C. Activation of NOD2 in HEK293 cells overexpressing NOD2 induced the IL-17C promoter, an activity that was significantly reduced in cells overexpressing the Crohn's disease-associated NOD2 mutation 3020insC (1007fs) or the Crohn's disease- and atopic dermatitis-associated NOD2-R702W variant. The first NF-κB-binding site in the IL-17C promoter was critical for NOD2-mediated IL-17C induction. Infection of human primary keratinocytes with S. aureus induced NOD2 and IL-17C gene expression. Overexpression of NOD2 in keratinocytes augmented S. aureus-mediated IL-17C gene expression as compared with NOD2-R702W overexpression. S. aureus-induced IL-17C expression was diminished in NOD2 small interfering RNA (siRNA)-treated keratinocytes. Moreover, significantly less S. aureus bacteria survived in keratinocytes overexpressing NOD2 but not in cells overexpressing the NOD2-R702W variant. Finally, S. aureus showed an increased survival in keratinocytes treated with NOD2 or IL-17C siRNA. In summary, our study provides evidence that S. aureus activates NOD2 in keratinocytes, resulting in an increased expression of IL-17C, a mechanism that may be dysregulated in atopic dermatitis.
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Roth
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Simanski
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Rademacher
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Schröder
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany. Electronic address: jharder@dermatology.uni-kiel.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Harder
mesh_terms: D003876:Dermatitis, Atopic / Q000276:immunology / Q000382:microbiology; D015870:Gene Expression / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology* / Q000382:microbiology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*
chemical_list: C515925:IL17C protein, human; D020381:Interleukin-17; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D034741:RNA, Small Interfering
references.citation: FEMS Microbiol Lett. 2009 Jan;290(2):149-55
references.pmid: 19054079
references.citation: Arch Dermatol Res. 2006 Mar;297(9):409-11
references.pmid: 16402184
references.citation: J Am Acad Dermatol. 1995 Jun;32(6):982-6
references.pmid: 7751469
references.citation: Nat Rev Immunol. 2011 Nov 18;11(12):805
references.pmid: 22094986
references.citation: FASEB J. 2010 Oct;24(10):4089-102
references.pmid: 20522786
references.citation: J Invest Dermatol. 2013 Jan;133(1):17-26
references.pmid: 22673731
references.citation: J Am Chem Soc. 2012 Aug 22;134(33):13535-7
references.pmid: 22857257
references.citation: Mucosal Immunol. 2011 Sep;4(5):484-95
references.pmid: 21750585
references.citation: Semin Immunopathol. 2012 Mar;34(2):261-80
references.pmid: 22057887
references.citation: Mucosal Immunol. 2008 Nov;1 Suppl 1:S67-74
references.pmid: 19079235
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12873-8
references.pmid: 19541630
references.citation: J Allergy Clin Immunol. 2003 Apr;111(4):813-7
references.pmid: 12704363
references.citation: Nat Immunol. 2011 Oct 12;12(12):1151-8
references.pmid: 21993849
references.citation: Dermatology. 2006;212(1):19-22
references.pmid: 16319468
references.citation: Rheumatol Int. 2012 Jul;32(7):1893-900
references.pmid: 21448648
references.citation: J Dermatol Sci. 2006 Jun;42(3):203-14
references.pmid: 16679003
references.citation: Infect Immun. 2004 Oct;72(10):5668-75
references.pmid: 15385465
references.citation: J Biol Chem. 2011 Jul 22;286(29):25487-94
references.pmid: 21628458
references.citation: Immunity. 2006 Jan;24(1):79-91
references.pmid: 16413925
references.citation: J Biol Chem. 2006 Jan 27;281(4):2005-11
references.pmid: 16319062
references.citation: J Leukoc Biol. 2005 Apr;77(4):476-86
references.pmid: 15629886
references.citation: J Immunol. 2000 Nov 15;165(10):5392-6
references.pmid: 11067888
references.citation: Adv Dermatol. 2008;24:71-87
references.pmid: 19256306
references.citation: Inflamm Bowel Dis. 2003 Jul;9(4):215-23
references.pmid: 12902844
references.citation: J Invest Dermatol. 2011 Feb;131(2):382-90
references.pmid: 21048787
references.citation: Exp Dermatol. 2007 Aug;16(8):692-8
references.pmid: 17620097
references.citation: Nat Immunol. 2011 Oct 12;12(12):1159-66
references.pmid: 21993848
references.citation: Cell Microbiol. 2008 Jan;10(1):1-8
references.pmid: 17944960
references.citation: Br J Dermatol. 2009 Feb;160(2):297-304
references.pmid: 19016710
references.citation: J Biol Chem. 2001 Feb 16;276(7):4812-8
references.pmid: 11087742
references.citation: Br J Dermatol. 2009 Feb;160(2):319-24
references.pmid: 19016708
references.citation: Trends Immunol. 2012 Jul;33(7):343-9
references.pmid: 22476048