title: Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions.
abstract: The proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1β is mediated by inflammasomes; however, the mechanisms triggering IL-1β processing remain unknown. Recently, cytosolic DNA has been identified as a danger signal that activates inflammasomes containing the DNA sensor AIM2. In this study, we detected abundant cytosolic DNA and increased AIM2 expression in keratinocytes in psoriatic lesions but not in healthy skin. In cultured keratinocytes, interferon-γ induced AIM2, and cytosolic DNA triggered the release of IL-1β via the AIM2 inflammasome. Moreover, the antimicrobial cathelicidin peptide LL-37, which can interact with DNA in psoriatic skin, neutralized cytosolic DNA in keratinocytes and blocked AIM2 inflammasome activation. Together, these data suggest that cytosolic DNA is an important disease-associated molecular pattern that can trigger AIM2 inflammasome and IL-1β activation in psoriasis. Furthermore, cathelicidin LL-37 interfered with DNA-sensing inflammasomes, which thereby suggests an anti-inflammatory function for this peptide. Thus, our data reveal a link between the AIM2 inflammasome, cathelicidin LL-37, and autoinflammation in psoriasis, providing new potential targets for the treatment of this chronic skin disease.
authors.affiliation: Department of Dermatology and Allergy, Ludwig-Maximilian-University, 80337 Munich, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dombrowski
authors.forename: Mark
authors.initials: M
authors.lastname: Peric
authors.forename: Sarah
authors.initials: S
authors.lastname: Koglin
authors.forename: Claudia
authors.initials: C
authors.lastname: Kammerbauer
authors.forename: Christine
authors.initials: C
authors.lastname: Göss
authors.forename: David
authors.initials: D
authors.lastname: Anz
authors.forename: Maren
authors.initials: M
authors.lastname: Simanski
authors.forename: Regine
authors.initials: R
authors.lastname: Gläser
authors.forename: Jürgen
authors.initials: J
authors.lastname: Harder
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Robert
authors.initials: R
authors.lastname: Besch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schauber
mesh_terms: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism* / Q000473:pathology; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011565:Psoriasis / Q000378:metabolism* / Q000473:pathology*
chemical_list: C410167:AIM2 protein, human; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D009687:Nuclear Proteins; D004247:DNA