Inflammasome Activation Mechanisms in Immune Responses

Inflammasomes are multiprotein platforms that detect pathogenic or damage‐associated signals within the cytosol and coordinate innate immune responses through caspase-1 activation, the processing of interleukin-1β and interleukin-18, and induction of pyroptotic cell death. Activation generally follows a two-signal model: a priming step, often driven by pattern-recognition receptors or cytokine-receptor engagement, elevates expression and post-translational readiness of sensor proteins; a subsequent activation step, triggered by a diverse set of stimuli such as ion flux, reactive oxygen species or effector proteins, induces assembly of the sensor, adaptor and effector components into a supramolecular inflammasome complex. Fine-tuning of these processes is governed by spatial organisation at organelle contact sites, by reversible modifications including phosphorylation, ubiquitination or UFMylation, and by feedback regulation via E3 ligases or deubiquitinases. Aberrant inflammasome activity is implicated in autoinflammatory syndromes, metabolic disorders, neurodegeneration and acute lung injury, highlighting both its physiological importance in host defence and its potential as a therapeutic target.

Research from Nature Portfolio

Recent studies have applied correlative cryo-light microscopy and cryo-electron tomography to visualise NLRP3-activated ASC assemblies in situ, revealing a branched filament network with a tubular pyrin-domain core that colocalises with Golgi-like vesicles and ribosomes. This structural insight emphasises the role of organelle interfaces in promoting caspase-1 recruitment and efficient cytokine maturation. Complementary work on the regulation of NLRP3 abundance has identified the E3 ubiquitin ligase TRIM31 as a feedback suppressor that tags NLRP3 for proteasomal degradation, thus restraining excessive inflammasome activation under homeostatic conditions. Earlier mechanistic studies of ASC oligomerisation have shown that filament formation creates numerous caspase-1 activation sites, serving as a signal‐amplification mechanism that bolsters cytokine release without necessarily affecting the execution of pyroptotic cell death.

Inflammasome Activation Mechanisms in Immune Responses publication trend

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

Technical terms

Inflammasome: A cytosolic protein complex that activates inflammatory caspases in response to danger signals.

NLRP3: A nucleotide-binding domain, leucine-rich repeat receptor that senses diverse stimuli as part of the NLRP3 inflammasome.

ASC: An adaptor protein containing pyrin and CARD domains that bridges sensor proteins to caspase-1.

Pyroptosis: A lytic form of programmed cell death driven by gasdermin-mediated pore formation and inflammatory cytokine release.

Ubiquitination: A reversible post-translational modification in which ubiquitin is attached to a protein, often marking it for degradation.

UFMylation: A ubiquitin-like modification involving Ufm1 conjugation that can stabilise proteins by preventing their autophagic degradation.

References

1. An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cellular & Molecular Immunology (2021).
2. Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization. Nature Communications (2023).
3. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nature Communications (2016).
4. ASC filament formation serves as a signal amplification mechanism for inflammasomes. Nature Communications (2016).
5. Inhibition of macrophage inflammasome assembly and pyroptosis with GC-1 ameliorates acute lung injury. Theranostics (2025).
6. UFMylation of NLRP3 Prevents Its Autophagic Degradation and Facilitates Inflammasome Activation. Advanced Science (2025).
7. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. Journal of Clinical Investigation (2016).