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Suppressive oligodeoxynucleotides containing TTAGGG motifs Inhibit cGAS activation in human monocytes

  1. Author:
    Steinhagen, Folkert
    Zillinger, Thomas
    Peukert, Konrad
    Fox, Mario
    Thudium, Marcus
    Barchet, Winfried
    Putensen, Christian
    Klinman, Dennis
    Latz, Eicke
    Bode, Christian

  2. Author Address

    Department of Anesthesiology and Critical Care Medicine, University of Bonn, Bonn, Germany., Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany., German Center for Infection Research (DZIF), Cologne-Bonn, Germany., Cancer and Inflammation Program, Center for Cancer Research, NCI, Frederick, MD, USA., Institute of Innate Immunity, University of Bonn, Bonn, Germany.,
    1. Year: 2018
    2. Date: Apr
    3. Epub Date: 2017 12 07
  2. Journal: European journal of immunology
    1. 48
    2. 4
    3. Pages: 605-611
  4. Type of Article: Article
  5. ISSN: 0014-2980
  1. Abstract:

    Type I interferon (IFN) is a critical mediator of autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi-Goutières Syndrome (AGS). The recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of type I IFN in response to cytosolic DNA and is potentially linked to SLE and AGS. Suppressive oligodeoxynucleotides (ODN) containing repetitive TTAGGG motifs present in mammalian telomeres have proven useful in the treatment of autoimmune diseases including SLE. In this study, we demonstrate that the suppressive ODN A151 effectively inhibits activation of cGAS in response to cytosolic DNA, thereby inhibiting type I IFN production by human monocytes. In addition, A151 abrogated cGAS activation in response to endogenous accumulation of DNA using TREX1-deficient monocytes. We demonstrate that A151 prevents cGAS activation in a manner that is competitive with DNA. This suppressive activity of A151 was dependent on both telomeric sequence and phosphorothioate backbone. To our knowledge this report presents the first cGAS inhibitor capable of blocking self-DNA. Collectively, these findings might lead to the development of new therapeutics against IFN-driven pathologies due to cGAS activation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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External Sources

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  2. DOI: 10.1002/eji.201747338
  3. PMID: 29215161
  4. View record in Web of Science®
  5. WOS: 000430105600007

Library Notes

  1. Fiscal Year: FY2017-2018
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