The role of AIM2 inflammasome in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with heterogeneous clinical manifestations, disease course and prognosis. Whilst lupus is originally considered to be a B and T cell-mediated disease, growing evidence highlights the critical involvement of dysregulated innate immune responses in SLE aethiopathogenesis. The inflammasomes are multiprotein complexes which oligomerise in the cytosol of monocytes/macrophages to trigger innate inflammatory responses against pathogenic ligands or endogenous stressors. An inflammasome comprises of a pattern recognition receptor (PRR), an adaptor protein named apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and a caspase-1 (CASP1) effector which cleaves and activates two potent proinflammatory cytokines, interleukin (IL)-1β and IL-18. Notably, elevated levels of IL-1β and IL-18 have been detected in the skin, kidneys and sera of SLE patients. Absent in Melanoma 2 (AIM2), which uniquely senses double-stranded DNA (dsDNA), is one of the few known PRRs that induces the assembly of inflammasomes. Although the accumulation of endogenous dsDNA (SLE autoantigen) is well documented in SLE, the role of AIM2 inflammasome remains controversial in murine SLE, and is poorly understood in human SLE. Therefore, current study aimed to characterise the functional role of AIM2 inflammasome in SLE patients.

Firstly, gene expression of AIM2, ASC and CASP1 were found significantly higher in SLE monocytes than healthy control (HC) monocytes. Secondly, SLE monocytes were found to exhibit augmented production of IL-1β and IL-18 by AIM2 inflammasome. Together, current study revealed an anomalous state of the AIM2 inflammasome in SLE patients. Additionally, dysregulated expression of the AIM2 inflammasome components were associated with lower platelet count, haemoglobin level and the use of hydroxychloroquine in SLE patients. Next, I showed that SLE serum could upregulate both mRNA and protein levels of AIM2 in healthy monocytes, and correspondingly, mediate higher AIM2 inflammasome activity. Type I IFNs was later delineated to be the pathogenic factor which could potentiate AIM2 inflammasome response in human monocytes through upregulating AIM2 expression. Transcriptional profiling further revealed elevated expression of signal transducer and activator of transcription (STAT) 1 and STAT2, in SLE monocytes, which might in turn regulate AIM2 expression. Using chromatin immunoprecipitation assay, I confirmed that type I IFNs could increase the binding of these two transcription factors to an ISRE (interferon-stimulated regulatory element)-like site in AIM2 promoter to mediate higher gene expression.

This study demonstrates that the dysregulation of AIM2 inflammasome in SLE patients is mediated by elevated levels of type I IFNs. Additionally, these findings further support the pathogenic role of type I IFNs in SLE development through a novel mechanism by which AIM2 inflammasome response is amplified via the STAT1/STAT2/AIM2 axis in monocytes. Hitherto, there is no cure for lupus and patients are mainly managed using corticosteroids and immunosuppressants. Hence, novel inhibitors targeting AIM2 and its upstream TFs (STAT1/2) or type I IFNs might constitute an alternate strategy to help dampen chronic inflammation and damage in SLE patients, especially those with high levels of IL-1β and IL-18.