The AIM2 inflammasome was initially identified as a sensor of cytoplasmic double-stranded DNA of host or pathogen origin (Fig. 1). AIM2 recognizes self-DNA after disruption of nuclear envelope integrity. In addition, AIM2 can sense DNA damage in the nucleus in the context of irradiation or cytostatic drug treatment. Host DNA can also be available outside the cell as a result of necrosis or neutrophil extracellular trap (NET) formation. Indeed, NETs induce IL-1β release from macrophages, a process that is connected to the aggravation of atherosclerosis in mice5. Mechanistic evidence indicates that AIM2 recognizes NET-DNA6. However, it is not clear how extracellular DNA is shuttled across the plasma membrane to be available for AIM2 sensing. In addition, histones in NET-DNA are heavily citrullinated, and the effect of this modification on DNA sensing requires further analysis.

The AIM2 inflammasome is activated by double-stranded DNA (dsDNA) derived from bacteria, DNA viruses or dead cells. Neutrophils release neutrophil extracellular traps (NETs) in the arterial lumen at sites of disturbed blood flow or in the atherosclerotic lesion. NET-DNA can interact with the AIM2 inflammasome. SARS-CoV-2 or influenza A virus can indirectly activate AIM2 by inducing cell death or by association with bacterial co-infection. Intracellularly, mitochondrial damage and nuclear dsDNA can activate AIM2 leading to the generation of IL-1β and IL-18 as well as the formation of gasdermin D pores. ROS, reactive oxygen species.

Epidemiological studies indicate a striking increase in the short-term risk of cardiovascular disease after bacterial or viral infection. As an example, acute respiratory tract infection with Staphylococcus aureus or Streptococcus pneumoniae transiently increases the risk of an acute coronary syndrome up to 20-fold. Given that both pathogens are sensed by the AIM2 inflammasome, one might speculate that AIM2 activation links bacterial infection with cardiovascular complications. In addition, the COVID-19 pandemic has epitomized the connection between viral infections and cardiovascular complications. This connection is not new because such a relationship was observed more than a century ago during the 1918 influenza pandemic. Neither SARS-CoV-2, which causes COVID-19, nor influenza A virus triggers AIM2 activation directly, but they might do so indirectly through accumulation of dead cells or bacterial co-infection7.

“the AIM2 inflammasome might be an important target for precision medicine”

In mice with Jak2VF-accelerated atherosclerosis, increased macrophage proliferation and increased glycolytic flux with higher mitochondrial production of reactive oxygen species (ROS) seem to promote AIM2 inflammasome activation3. Increased ROS production and oxidative DNA damage occur upstream of AIM2 inflammasome activation, because these changes were further increased in Jak2VF-expressing macrophages that were deficient in caspase 1–caspase 11 or gasdermin D3. Increased ROS levels and oxidative DNA damage have been implicated in activation of both the NLRP3 inflammasome8 and the AIM2 inflammasome9, and activation of both inflammasomes was increased in human and mouse JAK2VF macrophages. However, experiments using Jak2VFNlrp3−/− mice and Jak2VFAim2−/− mice showed that, in vivo, the AIM2 inflammasome has a more predominant role than the NLRP3 inflammasome in promoting atherosclerosis3. This specificity was explained by increased levels of AIM2 in plaque macrophages and bone marrow-derived macrophages in Jak2VF mice, whereas NLRP3 levels were reduced3. Type 1 interferons induce Aim2 expression, and increased Aim2 mRNA in mouse Jak2VF macrophages was dependent on interferon-γ (IFNγ)3, which is induced downstream of JAK–STAT signalling in Jak2VF cells. Given that macrophage proliferation and glycolytic flux are commonly increased in atherosclerosis and that IFNγ levels increase in standard mouse models of atherosclerosis, similar mechanisms are likely to underlie a broader role of AIM2 inflammasome activation in atherosclerosis than previously appreciated.