title: Human plasmacytoid dentritic cells elicit a Type I Interferon response by sensing DNA via the cGAS-STING signaling pathway.
abstract: Plasmacytoid dendritic cells (pDCs) are a major source of type I interferon (IFN) and are important for host defense by sensing microbial DNA via TLR9. pDCs also play a critical role in the pathogenesis of IFN-driven autoimmune diseases. Yet, this autoimmune reaction is caused by the recognition of self-DNA and has been linked to TLR9-independent pathways. Increasing evidence suggests that the cytosolic DNA receptor cyclic GMP-AMP (cGAMP) synthase (cGAS) is a critical component in the detection of pathogens and contributes to autoimmune diseases. It has been shown that binding of DNA to cGAS results in the synthesis of cGAMP and the subsequent activation of the stimulator of interferon genes (STING) adaptor to induce IFNs. Our results show that the cGAS-STING pathway is expressed and activated in human pDCs by cytosolic DNA leading to a robust type I IFN response. Direct activation of STING by cyclic dinucleotides including cGAMP also activated pDCs and knockdown of STING abolished this IFN response. These results suggest that pDCs sense cytosolic DNA and cyclic dinucleotides via the cGAS-STING pathway and that targeting this pathway could be of therapeutic interest.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Bonn, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bode
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Bonn, Bonn, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Fox
authors.affiliation: Laboratory of Experimental Immunology, Cancer Inflammation Program, Leidos Biomedical Research Inc, FNLCR, Frederick, MD, USA.
authors.forename: Poonam
authors.initials: P
authors.lastname: Tewary
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Steinhagen
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Bonn, Bonn, Germany.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Ellerkmann
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, NCI, Frederick, MD, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Klinman
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Bonn, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Baumgarten
authors.affiliation: Institute of Molecular Medicine, University of Bonn, Bonn, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Bonn, Bonn, Germany.
authors.forename: Folkert
authors.initials: F
authors.lastname: Steinhagen
mesh_terms: D002478:Cells, Cultured; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004247:DNA; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D051217:Toll-Like Receptor 9; C532857:STING1 protein, human; D000099197:STING Protein; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
keywords: Cytosolic sensor; DNA; Dentritic cells; Innate immunity; Interferon; Toll-like-receptors