AIM2 Inflammasome Dynamics in Innate Immune Responses

The absent in melanoma 2 sensor orchestrates a rapid inflammatory cascade upon detection of cytosolic double-stranded DNA, driving assembly of the AIM2 inflammasome. Engagement of the HIN (haematopoietic interferon-inducible nuclear) domain with foreign or damaged DNA relieves autoinhibition of the pyrin domain, enabling recruitment of the adaptor ASC and subsequent activation of Caspase 1. This triggers maturation and secretion of interleukin 1β and interleukin 18 and prompts gasdermin D–mediated membrane pore formation, culminating in pyroptotic cell death. The kinetics of filament nucleation, stabilisation and disassembly are finely regulated by oligomerisation interfaces, post-translational modifications and autophagic pathways. Moreover, diverse pathogens deploy inhibitor proteins to subvert inflammasome assembly, while host factors modulate inflammasome dynamics in tissue homeostasis, pathogen clearance and inflammatory pathology. A detailed understanding of these processes has profound implications for antiviral strategies, autoinflammatory disease management and therapeutic modulation of innate immunity.

Research from Nature Portfolio

Recent studies have uncovered a viral evasion mechanism whereby cytomegalovirus encodes a pyroptosis inhibitor that binds the pyrin domain of AIM2 and ASC, preventing filament formation and Caspase 1 activation. This interaction blocks interleukin 1β and interleukin 18 release and inhibits gasdermin D pore formation, thereby promoting viral replication in macrophages and murine models. Complementing this, seminal structural work has elucidated how AIM2 couples dsDNA binding and oligomerisation to generate a helical scaffold that templates downstream ASC filaments. This study revealed that both the pyrin-domain oligomers and the dsDNA-binding domain are essential for ligand-dependent inflammasome assembly rather than autoinhibition, offering a unifying model of signal propagation within the AIM2 inflammasome.

AIM2 Inflammasome Dynamics in Innate Immune Responses publication trend

The graph below shows the total number of articles in aim2 inflammasome dynamics in innate immune responses across all publications each year (not limited to Nature Index journals).

Technical terms

AIM2: A cytosolic sensor of double-stranded DNA that initiates inflammasome assembly.

Inflammasome: A multiprotein complex that activates inflammatory caspases for cytokine maturation and pyroptosis.

Pyrin domain (PYD): A protein–protein interaction module in AIM2 and ASC essential for homotypic filament formation.

ASC: Apoptosis-associated speck-like protein containing a caspase recruitment domain, which bridges sensor and effector caspases.

Pyroptosis: A lytic form of programmed cell death mediated by gasdermin pores and inflammatory cytokine release.

Oligomerisation: The self-association of sensor or adaptor proteins into filamentous structures that amplify immune signals.

References

1. A cytomegalovirus inflammasome inhibitor reduces proinflammatory cytokine release and pyroptosis. Nature Communications (2024).
2. Filament assembly underpins the double-stranded DNA specificity of AIM2-like receptors. Nucleic Acids Research (2023).
3. Autophagy‐mediated activation of the AIM2 inflammasome enhances M1 polarization of microglia and exacerbates retinal neovascularization. MedComm (2024).
4. Assembly-driven activation of the AIM2 foreign-dsDNA sensor provides a polymerization template for downstream ASC. Nature Communications (2015).