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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-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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95474 | GEO | 2017/03/01

SECONDARY ACCESSION(S): PRJNA377232

REPOSITORIES: GEO

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Non-lesional and Lesional Lupus Skin Share Inflammatory Phenotypes that Drive Activation of CD16+ Dendritic Cells

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2022-03-25 | GSE186476 | GEO

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AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II deficient mice

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2011-06-14 | GSE29938 | GEO

Targeted protein expression analysis of skewed or drug-treated mouse T cells, and of serum from first disease vs flare in a model of Cutaneous Lupus Erythematosus

Project description:We performed targeted protein expression analysis on cultured Th0, Th1 and Th2 cells, and on T cells treated with known drug triggers of cutaneous lupus erythematosus (CLE). In tandem, we performed targeted protein expression analysis on serum from first vs flare Th2-injected mice in the CLE model.

2022-06-01 | GSE186095 | GEO

Loss of Trex1 in dendritic cells is sufficient to trigger systemic autoimmunity

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2016-08-01 | E-GEOD-77693 | biostudies-arrayexpress

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