Pathway
NLRP3 Inflammasome
Last updated Sat May 30 2026 00:00:00 GMT+0000 (Coordinated Universal Time)
RCT evidence— CANTOS trial validated inflammasome targeting
What it is
The NLRP3 inflammasome is a cytosolic multimer that assembles when NLRP3 senses a wide range of danger signals (cholesterol crystals, urate crystals, amyloid-β, mtDNA, K+ efflux). Assembled NLRP3 + ASC + pro-caspase-1 forms a platform that activates caspase-1, which:
- Cleaves pro-IL-1β and pro-IL-18 into mature cytokines.
- Cleaves gasdermin D → pyroptotic cell death.
- Drives a powerful inflammatory cascade.
Why it matters in aging
NLRP3 activation rises with age. It is a central driver of:
- Atherosclerosis (cholesterol crystals).
- Gout (urate crystals).
- Type-2 diabetes (islet amyloid, fatty acids).
- Alzheimer's disease (amyloid-β).
- Age-related macular degeneration.
- Chronic kidney disease.
The CANTOS trial showed that monoclonal-antibody blockade of IL-1β (canakinumab) reduces cardiovascular events in post-MI patients with high hsCRP — the first large outcomes trial validating inflammasome targeting in cardiovascular disease.
Pharmacology
- Canakinumab (anti-IL-1β) — approved for autoinflammatory syndromes; CANTOS proof-of-concept in CVD.
- Anakinra (recombinant IL-1Ra) — daily subcutaneous; used in pericarditis, Still's disease.
- Rilonacept (IL-1 trap).
- Direct NLRP3 inhibitors (MCC950 / CRID3, dapansutrile) in clinical trials.
- Colchicine — partially inhibits NLRP3 assembly; cardiovascular benefit shown in LoDoCo2.
Related entries
Chronic inflammation, NF-κB, CANTOS, Canakinumab, Low-dose colchicine.
References
- Mangan, M. S. J. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discov. 17, 588–606 (2018).
- Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).