Control of type I interferon responses by the AIM2 inflammasome

Abstract

Abstract The immune system considers the presence of DNA in the cytosol as a sign of potential pathogen invasion and mounts inflammatory responses. Cytosolic DNA can be sensed by cyclic GMP-AMP synthase (c-GAS) leading to the production of type I Interferons (IFN). It can also be recognized by the PYHIN DNA sensor absent in melanoma (AIM2) resulting in the activation of inflammasome responses i.e. production of pro-inflammatory cytokines IL-1β and IL-18 as well as pyroptosis. Our results show that AIM2 inflammasome activation limits the production of type I IFNs in immune cells such as macrophages and dendritic cells. Further analysis showed that the recognition of cytosolic DNA and the assembly of inflammasome complex appear to be required for AIM2 regulation of IFN-β. Biochemical evidence showed an augmented phosphorylation of the transcription factor IRF-3 resulting in increased IFN-β production in AIM2-deficient macrophages. These findings may have implications in the treatment of autoimmune disorders such as systemic lupus erythematosus (SLE) associated with unregulated type I IFN signaling. (Supported by NIH R01AI119015 and Charles Hood Child Health Research Award)