Caspase Signaling in Innate Immune Responses

Caspases constitute a family of cysteine proteases that orchestrate programmes of cell death and inflammatory signalling in innate immunity. Among these, inflammatory caspases such as caspase-1, ‑4 and ‑5 in humans (and caspase-11 in mice) drive cytokine maturation and a lytic programme known as pyroptosis, whereas apoptotic caspases (notably caspase-8) also partake in non-apoptotic roles. Activation typically occurs within multiprotein platforms termed inflammasomes, which assemble in response to pathogen- or damage-associated molecular patterns. Once recruited, inflammatory caspases cleave pro-interleukin-1β and pro-interleukin-18 into their bioactive forms and process the pore-forming protein gasdermin D, leading to rapid membrane permeabilisation and release of cytokines. Beyond this canonical pathway, caspase-8 can act as both an initiator of apoptosis and a scaffold to promote inflammasome assembly, revealing a flexible network of cross-talk between apoptotic, pyroptotic and necroptotic programmes. This coordination ensures efficient microbial clearance, limits pathogen dissemination and shapes downstream adaptive responses, while dysregulation can precipitate inflammatory diseases.

Research from Nature Portfolio

Recent studies have delineated a non-enzymatic role for caspase-8 in driving assembly of the NLRP3 inflammasome downstream of double-stranded RNA sensing. Following engagement of TLR3 or related cytosolic receptors, FADD and RIPK1 recruit caspase-8 as a scaffold to provide a priming signal that licences inflammasome formation independently of its protease activity. A second, MLKL-dependent pathway involving RIPK3 then furnishes both priming and activation signals, culminating in full NLRP3 oligomerisation. This work redefines caspase-8 as an adaptor molecule essential for post-translational activation of innate immune responses to nucleic acids, extending its functional landscape well beyond apoptotic initiation.

Caspase Signaling in Innate Immune Responses publication trend

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

Technical terms

Caspase: A cysteine protease that cleaves substrates after aspartate residues, regulating cell death or cytokine processing.

Inflammasome: A multiprotein complex that activates inflammatory caspases in response to microbial or danger signals.

Pyroptosis: A form of pro-inflammatory cell death driven by inflammasome-activated caspases and gasdermin D pore formation.

NLRP3: A nucleotide-binding receptor that nucleates inflammasome assembly upon sensing diverse stimuli.

Necroptosis: A regulated form of necrosis mediated by receptor-interacting kinases and characterised by membrane disruption.

Scaffolding function: Non-enzymatic role of a protein in organising signalling complexes for downstream activation.

References

1. Inflammasome activation occurs in CD4+ and CD8+ T cells during graft-versus-host disease. Cell Death & Disease (2023).
2. The dance of macrophage death: the interplay between the inevitable and the microenvironment. Frontiers in Immunology (2024).
3. Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. Nature Communications (2015).
4. Flexible Usage and Interconnectivity of Diverse Cell Death Pathways Protect against Intracellular Infection. Immunity (2020).