Serum type I interferon promotes AIM2 inflammasome dysregulation in lupus patients through STAT1 and STAT2

The Absent in Melanoma 2 (AIM2) inflammasome is a crucial producer of IL-1β and IL-18 upon sensing double-stranded (ds)DNA but its role in SLE remains ambiguous. The study aims to investigate the involvement and underlying mechanism leading to AIM2 inflammasome dysregulation in lupus patients.

Expression and functional response of AIM2 inflammasome in monocytes were compared between SLE patients and healthy controls. Serological factors affecting AIM2 inflammasome response were tested by in vitro culture of primary monocytes. RNA sequencing, bioinformatics analyses and chromatin-immunoprecipitation-coupled (ChIP)-qPCR were performed to identify downstream molecular targets mediating the dysregulation. The pathological impact of monocytic AIM2 dysregulation on SLE development was evaluated using an induced-lupus mouse model.

Monocytes of SLE patients exhibited elevated expression of AIM2 inflammasome components and elevated IL-1β and IL-18 production. SLE patients' sera and recombinant interferon (IFN)-α could promote AIM2 inflammasome activity through augmenting AIM2 expression. Mechanistically, through increasing the expression and activation of signal transducer and activator of transcription (STAT) 1 and STAT2 in SLE monocytes, serum type-I IFN facilitated binding of STAT1, STAT2 and IRF9 to IFN-stimulated regulatory element (ISRE)-like sites in AIM2 promoter, thereby inducing higher AIM2 gene expression. Deficiency of AIM2 in monocytes alleviated SLE-like features in lupus mice.

A novel pathway by which serum type-I IFN propagates innate immune dysfunction in SLE via the STAT1-STAT2/AIM2 inflammasome axis in monocytes has been revealed.