Immunostimulatory endogenous nucleic acids drive the lesional inflammation in cutaneous lupus erythematosus

Cutaneous lupus erythematosus (CLE) is a photosensitive autoimmune disease characterized by a strong type-I-interferon (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 (eNA). We hypothesized that these eNA (RNA- and DNA-motifs) have the capacity to activate innate immune pathways in keratinocytes via pathogen-recognition-receptors (PRR). Gene expression analyses revealed 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 eNA. UV-stimulation enhances the immunogenicity of eNA 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 LE-typical inflammation. UV-irradiation supports this inflammation by generation of highly immunostimulatory DNA motifs (8-OHG). These findings explain the photosensitivity of lupus patients and identify pathways of the innate immune system as targets for future therapies. Lesional skin biopsies were taken from patients with active, untreated lupus skin disease (Chronic discoid lupus erythematosus = CDLE, n=6; subacute cutaneous lupus erythematosus = SCLE, n=5). Healthy control (HC) specimens were obtained from healthy skin of 5 patients undergoing plastic surgery. In every case, two 4mm punch biopsies were taken. One was flash-frozen in liquid nitrogen and afterwards processed for mRNA isolation and gene expression analyses. The second biopsy was fixed in 5% formalin solution overnight, and was proceeded for histological investigation.