title: Keratin 1 maintains skin integrity and participates in an inflammatory network in skin through interleukin-18.
abstract: Keratin 1 (KRT1) and its heterodimer partner keratin 10 (KRT10) are major constituents of the intermediate filament cytoskeleton in suprabasal epidermis. KRT1 mutations cause epidermolytic ichthyosis in humans, characterized by loss of barrier integrity and recurrent erythema. In search of the largely unknown pathomechanisms and the role of keratins in barrier formation and inflammation control, we show here that Krt1 is crucial for maintenance of skin integrity and participates in an inflammatory network in murine keratinocytes. Absence of Krt1 caused a prenatal increase in interleukin-18 (IL-18) and the S100A8 and S100A9 proteins, accompanied by a barrier defect and perinatal lethality. Depletion of IL-18 partially rescued Krt1(-/-) mice. IL-18 release was keratinocyte-autonomous, KRT1 and caspase-1 dependent, supporting an upstream role of KRT1 in the pathology. Finally, transcriptome profiling revealed a Krt1-mediated gene expression signature similar to atopic eczema and psoriasis, but different from Krt5 deficiency and epidermolysis bullosa simplex. Our data suggest a functional link between KRT1 and human inflammatory skin diseases.
authors.affiliation: Translational Centre for Regenerative Medicine and Institute of Biology, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Wera
authors.initials: W
authors.lastname: Roth
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.forename: Hans-Dietmar
authors.initials: HD
authors.lastname: Beer
authors.forename: Miriam
authors.initials: M
authors.lastname: Richter
authors.forename: Claudia
authors.initials: C
authors.lastname: Wohlenberg
authors.forename: Ursula
authors.initials: U
authors.lastname: Reuter
authors.forename: Sören
authors.initials: S
authors.lastname: Thiering
authors.forename: Andrea
authors.initials: A
authors.lastname: Staratschek-Jox
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.forename: Fatima
authors.initials: F
authors.lastname: Kreusch
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Julia
authors.initials: J
authors.lastname: Reichelt
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Magin
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002454:Cell Differentiation; D003896:Desmosomes / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D020382:Interleukin-18 / Q000378:metabolism*; D053556:Keratin-1 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D020836:Protein Structure, Quaternary; D009418:S100 Proteins / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D020382:Interleukin-18; D053556:Keratin-1; D009418:S100 Proteins; D020170:Caspase 1