Caspase-1 Activation in Innate Immune Responses

Caspase-1 is a prototypical inflammatory caspase central to innate host defence and inflammatory homeostasis. Upon detection of microbial or danger signals by pattern-recognition receptors of the NOD-like receptor family, sensor proteins such as NLRP3, NLRC4 or AIM2 oligomerise and recruit the adaptor ASC through pyrin-domain interactions. ASC subsequently nucleates filaments that engage procaspase-1 via its CARD domain, leading to proximity-induced autocatalysis and generation of the active p20/p10 heterodimer. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 to their mature forms for secretion, and processes gasdermin D to unleash a pore-forming N-terminal fragment that drives pyroptotic cell death. This cascade both restricts pathogen replication and primes adaptive immunity, while dysregulated activation underlies autoinflammatory syndromes, metabolic disorders and neurodegenerative diseases. Modulation of each step in this pathway offers opportunities for therapeutic intervention across a spectrum of infectious and sterile inflammatory conditions.

Research from Nature Portfolio

Recent work has dissected alternative cell-death fates downstream of the NLRC4 inflammasome. In macrophages lacking catalytic caspase-1 activity, the NLRC4 sensor can redirect signalling through ASC to activate caspase-8, initiating an apoptotic programme that culminates in secondary membrane damage independently of gasdermin D. Genetic separation of caspase-1 enzymatic function and ASC engagement has illuminated the molecular branching between pyroptosis and apoptosis, revealing that sensor-initiated platforms can adapt flexibly to ensure cell-death execution when one inflammatory caspase is compromised.

Caspase-1 Activation in Innate Immune Responses publication trend

The graph below shows the total number of articles in caspase-1 activation in innate immune responses across all publications each year (not limited to Nature Index journals).

Technical terms

Inflammasome: A multiprotein complex that assembles in the cytoplasm to activate inflammatory caspases in response to danger or pathogen signals.

ASC: Apoptosis-associated speck-like protein containing a CARD; an adaptor that links sensor proteins to procaspase-1 via domain-domain interactions.

Pyroptosis: A lytic, pro-inflammatory form of programmed cell death driven by gasdermin D pores following caspase-1 activation.

Gasdermin D: A pore-forming protein cleaved by caspase-1 to unleash its N-terminal domain, which perforates cell membranes.

IL-1β and IL-18: Pro-inflammatory cytokines processed by caspase-1 and secreted to orchestrate local and systemic immune responses.

References

1. ASC- and caspase-8-dependent apoptotic pathway diverges from the NLRC4 inflammasome in macrophages. Scientific Reports (2018).
2. The role of inflammasomes in human diseases and their potential as therapeutic targets. Signal Transduction and Targeted Therapy (2024).
3. Collab or Cancel? Bacterial Influencers of Inflammasome Signaling. Annual Review of Microbiology (2023).