Inflammasome Mechanisms in Central Nervous System Disorders

Inflammasomes are cytosolic multiprotein platforms that detect danger signals and orchestrate innate immune responses within the central nervous system (CNS). On activation by aggregated proteins, microbial motifs or cellular stress, these complexes recruit and activate caspase-1, leading to maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) and triggering pyroptotic cell death. Microglia, the resident immune cells of the brain, represent the principal site of inflammasome assembly, yet astrocytes, neurons and infiltrating myeloid cells can also contribute to inflammasome-mediated pathology. Aberrant inflammasome activation has been implicated in multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, stroke and traumatic brain injury. Excessive IL-1β release perpetuates neuroinflammation, disrupts blood–brain barrier integrity and accelerates neuronal loss. Conversely, regulated inflammasome activity contributes to debris clearance and tissue repair. Recent advances have illuminated regulatory checkpoints involving ubiquitin ligases, kinases and adaptor proteins that fine-tune inflammasome thresholds and pyroptotic outcome. Understanding these mechanisms is central to the development of targeted therapies aimed at restoring immune balance in CNS disorders of global significance.

Research from Nature Portfolio

Recent studies have demonstrated that the NF-κB regulatory protein A20 is a critical brake on microglial activation and NLRP3 inflammasome assembly. In experimental models, conditional deletion of A20 in microglia resulted in hyperactivation of the NLRP3 complex, elevated IL-1β secretion and exacerbation of multiple sclerosis–like pathology. A20-deficient microglia displayed increased susceptibility to inflammatory stimuli and impaired synaptic regulation, linking inflammasome dysregulation directly to neurodegenerative sequelae. These findings underscore the importance of host ubiquitin-mediated control of inflammasome signalling in preserving CNS homeostasis.

Inflammasome Mechanisms in Central Nervous System Disorders publication trend

The graph below shows the total number of articles in inflammasome mechanisms in central nervous system disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Inflammasome: A multiprotein complex that senses danger signals and activates inflammatory caspases, leading to cytokine maturation and pyroptosis.

Pyroptosis: A lytic form of programmed cell death driven by caspase-1 activation, characterised by cell swelling, membrane rupture and release of pro-inflammatory contents.

Microglia: Resident macrophage-like immune cells of the CNS that survey the environment, clear debris and mediate innate immune responses.

Caspase-1: An inflammatory protease that processes pro-IL-1β and pro-IL-18 into their active forms and initiates pyroptosis through gasdermin D cleavage.

References

1. Regulatory T cells alleviate myelin loss and cognitive dysfunction by regulating neuroinflammation and microglial pyroptosis via TLR4/MyD88/NF-κB pathway in LPC-induced demyelination. Journal of Neuroinflammation (2023).
2. IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitis. Cell Death & Disease (2023).
3. A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation. Nature Communications (2018).
4. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Molecular Medicine (2019).