Effect of immunosuppressive oligodeoxynucleotide A151 on inflammasome activation pathways

Thesis Type: Postgraduate

Institution Of The Thesis: Orta Doğu Teknik Üniversitesi, Faculty of Arts and Sciences, Department of Biology, Turkey

Approval Date: 2017


Consultant: MAYDA GÜRSEL


Inflammasome activation is triggered by pathogen associated molecular patterns (PAMPs) and/or host derived danger associated molecular patterns (DAMPs) leading to caspase-1 (canonical) or caspase-11/caspase-4/5 activation (non-canonical) pathways stimulating IL-1β and IL-18 secretion. Excessive inflammasome activation has been associated with the pathogenesis of neurodegenerative and metabolic disorders as well as the macrophage activation syndrome (MAS) and cryopyrin associated periodic syndromes (CAPS). H syndrome, is another rare disease arising due to mutations in the genes encoding hENT3 (human equilibrative nucleoside transporter). This syndrome shares common symptoms with the inflammasome overactivation associated disorders CAPS and MAS which might suggest a common mechanistic origin of these diseases and the pathogenesis of H syndrome. The existence of these inflammasome overactivation related disorders necessitates the development of therapeutic agents targeting distinct pathways of inflammasome activation. Synthetic oligodeoxynucleotide (ODN) A151 expressing immunosuppressive TTAGGG motifs has been shown to ameliorate various inflammatory responses. In this study, we observed a significant decrease in IL-1β secretion and percent cytotoxicity of A151-ODN treated cells in AIM2, NLRC4, non-canonically activated, and nucleic acid induced NLRP3 inflammasomes but not in bacterial toxin stimulated NLRP3 inflammasome formation. Furthermore, we demonstrate a decrease in the release of ASC specks and inhibition of mitochondrial stress in A151 ODN treated samples. These are encouraging results for the potential therapeutic immunosuppressive effects of A151 ODN on dysregulated inflammasome complex formation. Finally, preliminary experiments using PBMC from an H syndrome patient suggested that autoinflammatory manifestations in this disease might in part be associated with over-active inflammasome formation.