Inflammasome Activation in Autoinflammatory Disorders

Autoinflammatory disorders arise from innate immune dysregulation in the absence of autoantibodies or autoreactive T cells. Central to many of these conditions is the aberrant activation of inflammasomes, cytosolic multiprotein platforms that detect pathogenic or sterile danger signals. On sensing triggers such as microbial toxins, metabolic perturbations or cytoskeletal damage, pattern recognition receptors—including NLRP3 and pyrin—undergo oligomerisation. This process recruits the adaptor ASC and pro-caspase-1, leading to caspase-1 activation, proteolytic maturation of interleukin-1β and interleukin-18, and execution of pyroptotic cell death via gasdermin D pore formation. Genetic variants in sensors or regulatory components can lower activation thresholds, causing recurrent fever, serositis, rash and arthralgia. Pyrin-related syndromes exemplify how MEFV mutations disturb inhibitory phosphorylation and 14-3-3 binding, whereas NLRP3 gain-of-function variants underlie cryopyrin-associated periodic syndromes. Recent advances in understanding post-translational and epigenetic regulation, as well as the interplay between autophagy and inflammasome clearance, have opened avenues for targeted therapies. Clinically, IL-1 blockade and colchicine remain mainstays, but emerging small-molecule inhibitors and RNA-based interventions promise greater precision. The global burden of autoinflammatory disease, spanning paediatric and adult presentations, underscores the need to elucidate inflammasome regulation for improved diagnostics and personalised treatment.

Research from Nature Portfolio

Recent studies have revealed that defects in cytoskeletal regulators can amplify inflammasome activity. Work on Wiskott-Aldrich syndrome protein deficiency demonstrates that impaired actin remodelling undermines autophagic removal of activated inflammasomes, resulting in excessive interleukin-1β release and cell death. This mechanistic insight identifies targets within the autophagy–inflammasome axis for potential intervention. Complementing this, investigations into microRNA control have shown that miR-197-3p directly modulates IL-1 receptor expression, attenuating caspase-1 activation and cytokine secretion in monocytes and fibroblasts. These findings underscore epigenetic layers of inflammasome regulation and suggest novel therapeutic strategies beyond protein blockade.

Inflammasome Activation in Autoinflammatory Disorders publication trend

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

Technical terms

Inflammasome: A cytosolic multiprotein complex that activates caspase-1 and drives maturation of pro-inflammatory cytokines.

Autoinflammatory disorder: A condition caused by innate immune activation without adaptive immune involvement, characterised by recurrent inflammation.

Pyrin: An inflammasome sensor encoded by MEFV that detects changes in Rho GTPase activity and regulates interleukin-1β release.

NLRP3: A nucleotide-binding domain, leucine-rich repeat receptor that forms an inflammasome in response to diverse stress signals.

Pyroptosis: A lytic form of programmed cell death mediated by gasdermin D pore formation following inflammasome activation.

References

1. How to Build a Fire: The Genetics of Autoinflammatory Diseases. Annual Review of Genetics (2023).
2. Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation. Cell Death & Disease (2023).
3. A stress sensor, IRE1α, is required for bacterial-exotoxin-induced interleukin-1β production in tissue-resident macrophages. Cell Reports (2024).
4. A dominant pathogenic MEFV mutation causes atypical pyrin-associated periodic syndromes. JCI Insight (2023).
5. The NLRP3 and Pyrin Inflammasomes: Implications in the Pathophysiology of Autoinflammatory Diseases. Frontiers in Immunology (2017).
6. Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients. EMBO Molecular Medicine (2019).
7. Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells. Nature Communications (2017).
8. Familial Mediterranean fever-related miR-197-3p targets IL1R1 gene and modulates inflammation in monocytes and synovial fibroblasts. Scientific Reports (2021).