title: Immunostimulatory Endogenous Nucleic Acids Drive the Lesional Inflammation in Cutaneous Lupus Erythematosus.
abstract: Cutaneous lupus erythematosus (CLE) is a photosensitive autoimmune disease characterized by a strong type I IFN-associated inflammation. Keratinocytes are known to determine the interface dermatitis pattern in CLE by production of proinflammatory cytokines in the lower epidermis. These cytokines drive a cytotoxic anti-epithelial immune response resulting in keratinocytic cell death and release of endogenous nucleic acids. We hypothesized that these endogenous nucleic acids (RNA and DNA motifs) have the capacity to activate innate immune pathways in keratinocytes via pathogen recognition receptors. Gene expression analyses showed an excessive activation of innate immune response pathways with strong expression of IFN-regulated cytokines in CLE skin lesions. Cultured keratinocytes produce large amounts of these cytokines in response to stimulation of PRR with endogenous nucleic acids. UV stimulation enhances the immunogenicity of endogenous nucleic acids and induces CLE-like skin lesions in knockout mice lacking the cytosolic DNase TREX1. Our results provide evidence for a pathogenetic role of endogenous nucleic acids in CLE. They are released within the cytotoxic inflammation along the dermo-epidermal junction and have the capacity to drive the CLE-typical inflammation. UV irradiation supports this inflammation by generation of highly immunostimulatory DNA motifs (8-hydroxyguanosine). These findings explain the photosensitivity of patients with lupus and identify pathways of the innate immune system as targets for future therapies.
authors.affiliation: Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Scholtissek
authors.affiliation: Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Zahn
authors.affiliation: Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Maier
authors.affiliation: Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Klaeschen
authors.affiliation: Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Braegelmann
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelzel
authors.affiliation: Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bieber
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.affiliation: Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany. Electronic address: joerg.wenzel@ukb.uni-bonn.de.
authors.forename: Joerg
authors.initials: J
authors.lastname: Wenzel
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015603:Keratinocytes / Q000378:metabolism; D008178:Lupus Erythematosus, Cutaneous / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D009696:Nucleic Acids / Q000378:metabolism*
chemical_list: D016207:Cytokines; D009696:Nucleic Acids