NLRP3 Inflammasome Activation in Immune Response

The NLRP3 inflammasome is a cytosolic multiprotein complex that serves as a central hub in innate immunity by sensing a wide array of pathogenic and sterile danger signals. Activation follows a two-step paradigm: a priming phase, during which transcriptional upregulation of inflammasome components and post-translational modifications prepare NLRP3 for assembly, and an activation phase, in which conformational changes drive oligomerisation. Assembly of NLRP3 with the adaptor ASC and pro-caspase-1 leads to caspase-1 auto-activation, cytokine maturation (IL-1β and IL-18) and gasdermin D–mediated pore formation, culminating in cytokine release and pyroptotic cell death. This cascade underpins host defence against infection but, when dysregulated, contributes to autoinflammatory, metabolic and neurodegenerative conditions. Recent advances have elucidated structural mechanisms governing inflammasome assembly, the interplay of cellular ion fluxes and reactive oxygen species, and the impact of post-translational modifications, highlighting novel regulatory checkpoints with therapeutic potential.

Research from Nature Portfolio

New findings have revealed that acetylation of NLRP3 at a conserved lysine residue is indispensable for full inflammasome activation. The enzyme KAT5 catalyses acetylation at lysine 24, promoting NLRP3 oligomerisation without affecting its recruitment to the trans-Golgi network. Genetic or pharmacological disruption of KAT5 activity markedly impairs caspase-1 activation and IL-1β release in vitro and in vivo, establishing the KAT5–NLRP3 axis as a targetable node in inflammatory disease.

Complementing this, mechanistic work has identified chloride intracellular channels (CLICs) as essential mediators downstream of potassium efflux and mitochondrial reactive oxygen species. Following inflammasome stimuli, mitochondrial ROS triggers translocation of CLICs to the plasma membrane, inducing chloride efflux that facilitates the NEK7–NLRP3 interaction, inflammasome assembly and caspase-1 activation. This chloride-efflux step emerges as a proximal upstream event in the canonical NLRP3 activation cascade.

NLRP3 Inflammasome Activation in Immune Response publication trend

The graph below shows the total number of articles in nlrp3 inflammasome activation in immune response across all publications each year (not limited to Nature Index journals).

Technical terms

NLRP3 inflammasome: A cytosolic sensor complex comprising NLRP3, ASC and pro-caspase-1 that triggers inflammatory cytokine release and pyroptosis.

Priming signal: Initial cue—often via pattern recognition receptors—that induces transcription and post-translational modifications of inflammasome components.

Caspase-1: A cysteine protease that cleaves pro-IL-1β and pro-IL-18 into their bioactive forms and processes gasdermin D to induce membrane pores.

Pyroptosis: A lytic form of programmed cell death associated with gasdermin D pore formation and inflammatory cytokine release.

Post-translational modification (PTM): Chemical alterations of proteins—such as acetylation or phosphorylation—that regulate activity, localisation or interactions.

NEK7: A serine/threonine kinase that binds to NLRP3 under low-potassium conditions, enabling inflammasome assembly.

ASC: An adaptor protein (apoptosis-associated speck-like protein containing a CARD) that links NLRP3 to pro-caspase-1 via homotypic domain interactions.

References

1. Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation. Annual Review of Immunology (2023).
2. Acetylation is required for full activation of the NLRP3 inflammasome. Nature Communications (2023).
3. Gelsolin alleviates rheumatoid arthritis by negatively regulating NLRP3 inflammasome activation. Cell Death & Differentiation (2024).
4. CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation. Nature Communications (2017).