University of Massachusetts Medical School Faculty Publications

Title

Synthetic oligodeoxynucleotides containing suppressive TTAGGG motifs inhibit AIM2 inflammasome activation

UMMS Affiliation

Department of Medicine, Division of Infectious Disease and Immunology

Publication Date

10-1-2013

Document Type

Article

Subjects

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

Disciplines

Immunity | Immunology and Infectious Disease

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-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.

Rights and Permissions

Citation: 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

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Journal of immunology (Baltimore, Md. : 1950)

PubMed ID

23986531