Inflammasome Activation in Innate Immune Responses

The innate immune system relies on intracellular sensor proteins to detect microbial motifs and danger signals. Upon recognition of such stimuli, nucleotide-binding oligomerisation domain-like receptors assemble into multiprotein platforms known as inflammasomes. These complexes recruit the adaptor ASC and promote activation of caspase-1, which in turn processes pro-inflammatory cytokines interleukin-1β and interleukin-18 and cleaves gasdermin D to generate membrane pores. Pore formation permits cytokine release and, in many cell types, initiates pyroptotic cell death. Although first characterised in macrophages, inflammasome biology in other innate cells—particularly neutrophils—reveals alternative trafficking of gasdermin D, autophagy-dependent secretion pathways and reversible pore formation. Tight regulation of inflammasome signalling is essential to clear pathogens, resolve sterile inflammation and prevent autoinflammatory and fibrotic disorders, making this pathway a focus for novel diagnostics and therapeutics.

Research from Nature Portfolio

Recent studies have delineated rapid, stimulus-specific activation of the NLRP3 inflammasome in neutrophils. Engagement of endothelial E-selectin triggers Bruton’s tyrosine kinase-dependent phosphorylation of NLRP3, concerted with potassium efflux through KV1.3 channels, leading to ASC oligomerisation, caspase-1 cleavage and transient gasdermin D pore formation. Notably, this mechanism enables controlled release of S100A8/S100A9 without cell death via recruitment of ESCRT III repair machinery. In bacterial keratitis models, Pseudomonas aeruginosa effectors differentially direct inflammasome subtype usage: ExoS ADP-ribosyltransferase activity skews neutrophil responses towards NLRP3, whereas macrophages rely on NLRC4. NLRP3 activation in neutrophils is essential for IL-1β secretion, bacterial killing and disease severity, highlighting an unexpected role for this pathway in ocular infection.

Inflammasome Activation in Innate Immune Responses publication trend

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

Technical terms

Inflammasome: A cytosolic multiprotein complex that activates caspase-1 upon detection of pathogens or cellular stress.

NLRP3: A member of the NOD-like receptor family that forms a canonical inflammasome in response to diverse stimuli.

ASC (apoptosis-associated speck-like protein containing a CARD): An adaptor protein essential for bridging sensor proteins to caspase-1 in inflammasomes.

Caspase-1: A cysteine protease activated by inflammasomes that cleaves cytokine precursors and gasdermin D.

Gasdermin D: A pore-forming effector protein whose N-terminal fragment mediates membrane permeabilisation and cytokine release.

Pyroptosis: An inflammatory form of programmed cell death driven by gasdermin D pore formation and cytokine release.

References

1. E-selectin-mediated rapid NLRP3 inflammasome activation regulates S100A8/S100A9 release from neutrophils via transient gasdermin D pore formation. Nature Immunology (2023).
2. NLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity. Nature Communications (2023).
3. Nanoreporter for Real‐Time Monitoring of Inflammasome Activity and Targeted Therapy. Advanced Science (2023).
4. Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death. Cell Reports (2018).
5. N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis. Nature Communications (2020).