Synthetic oligodeoxynucleotides containing suppressive TTAGGG motifs inhibit AIM2 inflammasome activation
Department of Medicine, Division of Infectious Disease and Immunology
Animals; Anti-Inflammatory Agents; Cell Line; Cluster Analysis; Cytoskeletal Proteins; Cytosol; DNA; DNA-Binding Proteins; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammasomes; Mice; Nuclear Proteins; *Nucleotide Motifs; Oligodeoxyribonucleotides; Protein Binding; Protein Multimerization; Signal Transduction; Thionucleotides
Immunity | Immunology and Infectious Disease
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-alpha, and ISG induction in response to cytosolic dsDNA. In addition, A151 abrogated caspase-1-dependent IL-1beta 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.
DOI of Published Version
J Immunol. 2013 Oct 1;191(7):3876-83. doi: 10.4049/jimmunol.1300530. Epub 2013 Aug 28. Link to article on publisher's site
Journal of immunology (Baltimore, Md. : 1950)
Kaminski, John J. III; Schattgen, Stefan A.; Tzeng, TeChen; Bode, Christian; Klinman, Dennis M.; and Fitzgerald, Katherine A., "Synthetic oligodeoxynucleotides containing suppressive TTAGGG motifs inhibit AIM2 inflammasome activation" (2013). University of Massachusetts Medical School Faculty Publications. 519.