Interferon-mediated AIM2 Inflammasome Dysfunction In Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder attributed by dysregulation in both innate and adaptive immune responses. Type I interferon (IFN) is considered as the central pathogenic cytokine in driving SLE development through its pleiotropic effects on various leukocytes including monocytes. In a study comparing the transcriptome profiles of monocytes exposed to sera from healthy subjects and SLE patients, genes of the NOD-like receptor signaling pathways, including the DNA-binding molecule, AIM2, were significantly enriched. The role of AIM2 in SLE is not completely clear and here we evaluated its function as a cytosolic autoantigen senor in activating the inflammasome activity to produce active IL-1β and IL-18 via the proteolytic activity of caspase-1. Compared with healthy individuals, monocytes from SLE patients exhibited higher expression of AIM2 and other inflammasome components caspase-1 and ASC; and concordantly produced higher levels of IL-1β and IL-18 upon stimulation with dsDNA. AIM2 expression in SLE monocytes also positively correlated with the expression of IFN-sensitive genes (ISGs) MX-1, IFIT-1 and LY6E. Healthy monocytes cultured in SLE serum induced higher AIM2 transcript expression and in positive correlation with ISGs induction. Furthermore, IFNα treatment induced expression of AIM2 mRNA together with increased inflammasome-induced IL-18 and IL-1β secretion in a dose-dependent manner. These findings suggest that dysregulated IFN-mediated AIM2 inflammasome activity may play a role in SLE pathogenesis. The molecular mechanism by which IFN mediates AIM2 induction is currently under investigation.