title: Synthetic oligodeoxynucleotides containing suppressive TTAGGG motifs inhibit AIM2 inflammasome activation.
abstract: Synthetic oligodeoxynucleotides (ODNs) comprised of the immunosuppressive motif TTAGGG block TLR9 signaling, prevent STAT1 and STAT4 phosphorylation and attenuate a variety of inflammatory responses in vivo. In this study, we demonstrate that such suppressive ODN abrogate activation of cytosolic nucleic acid-sensing pathways. Pretreatment of dendritic cells and macrophages with the suppressive ODN-A151 abrogated type I IFN, TNF-α, and ISG induction in response to cytosolic dsDNA. In addition, A151 abrogated caspase-1-dependent IL-1β and IL-18 maturation in dendritic cells stimulated with dsDNA and murine CMV. Inhibition was dependent on A151's phosphorothioate backbone, whereas substitution of the guanosine residues for adenosine negatively affected potency. A151 mediates these effects by binding to AIM2 in a manner that is competitive with immune-stimulatory DNA and as a consequence prevents AIM2 inflammasome complex formation. Collectively, these findings reveal a new route by which suppressive ODNs modulate the immune system and unveil novel applications for suppressive ODNs in the treatment of infectious and autoimmune diseases.
authors.affiliation: Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kaminski
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Schattgen
authors.forename: Te-Chen
authors.initials: TC
authors.lastname: Tzeng
authors.forename: Christian
authors.initials: C
authors.lastname: Bode
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D016000:Cluster Analysis; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D059372:Nucleotide Motifs; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013873:Thionucleotides / Q000737:chemistry
chemical_list: C540422:Aim2 protein, mouse; D000893:Anti-Inflammatory Agents; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides; D004247:DNA