NLRP3 inflammasome-driven disease

Associated DiseaseActivator and MechanismDisease and Pathologic FeatureGenetic and Pharmacologic InterventionRefa
Autoinflammatory disease
FCAS MWS NOMIDGain-of-function mutation in NACHT to disrupt autoinhibition of NLRP3Fever, neutrophilia, multiorgan inflammation (FCAS, MWS, NOMID).
Hearing loss (MWS, NOMID).
CNS inflammation (NOMID)
Autoinflammation in mice expressing CAPS variants.
Treatment by inhibition of IL-1 and NLRP3
IAVViral PAMPs and DAMPs
IAV M2 protein
HyperinflammationMCC950 protects juvenile mice from IAV hyperinflammation2
SARS-Cov-2Viral PAMPs and DAMPsAirway and lung inflammation in mild and severe SARS-Cov-2 patientsActivation of NLRP3 inflammasome in PBMCs and autopsy tissues3
Metabolic disease and aging
Obesity, type 2 diabetesCeramide, fatty acids, and obesity-associated DAMPsObesity, low-grade inflammation, fatty liver, insulin resistanceAblation of NLRP3 ↓ obesity-induced inflammation and insulin resistance4
AgingLow-grade inflammationSystemic low-grade inflammation and multiple aging phenotypes including ↓ lipolysis and ↑ SASPAblation of NLRP3 inflammasome protected from multiple, aging-driven phenotypes5
Common inflammatory/immune pathologic condition
AsthmaAllergic immune signals, nonallergic stimulantsAllergic airway inflammation in mice induced by ovalbumin or house dust mite extractAblation of the NLRP3 inflammasome pathway ↓ allergic airway inflammation.
MCC950 ↓ airway inflammation
IBDInflammatory DAMPsDSS-induced colitis in mice.
DNBS-induced colitis in rats
Ablation of NLRP3 ↓ severity of mouse colitis.
Inhibition of NLRP3 by INF39 ↓ severity of rat colitis
NAFLDFatty acid, cholesterolCholine deficient amino acid defined- or methionine/choline-deficient diet induced NAFLD in miceAblation of NLRP3 protected mice from induced NAFLD and fibrosis.
MCC950 ↓ induced NASH and liver scarring
RAInflammatory DAMPsSpontaneous erosive polyarthritis in A20(myol-KO) miceAblation of NLRP3 protected against rheumatoid arthritis-associated inflammation and cartilage destruction9
MS, EAEDAMPsAutoimmune encephalomyelitisAblation of NLRP3 led to resistance to EAE.
MCC950 ↓ the severity of EAE
Endogenous particulates-associated pathology
Gout and pseudogoutMSU or CPPD crystal
Phagocytosis and lysosomal disruption
Gout and pseudogout arthritis.
Urate or CPPD crystal-induced inflammation
Deficiency of NLRP3 inflammasome ↓ urate crystal-induced inflammation.
β-Hydroxybutyrate ↓ gouty flares by ↓ NLRP3 activation
AtherosclerosisCholesterol crystal
Phagocytosis and lysosomal disruption
Diet- and genetic-induced atherosclerosis; low-level inflammationAblation of NLRP3 and other genes ↓ atherosclerotic lesions in mice.
MCC950 ↓ atherosclerotic lesions
ADAβ fibril
Released by dead neurons; phagocytosed by microglia
Senile plaques in brain neurons.
Cerebral neuroinflammation.
Mouse APP/PS1 model
Activation of NLRP3 inflammasome by Aβ fibril.
Ablation of NLRP3 improves memory and clearance.
Fenamate NSAID and MCC950 protects against AD in mice
PDαSyn fibril
Released by dead neurons; phagocytosed by microglia
LB aggregates in dopaminergic neurons of substantial nigra
Loss of dopaminergic neurons
Activation of NLRP3 inflammasome by aSyn fibrils14
Exogenous particulates-associated pathology
ImmunizationAluminumPhagocytosis and lysosome disruptionEnhancing immunization effect as immunization adjuvant15
Silicosis, lung cancerCrystalline silica
Phagocytosis. lysosomal disruption. ↑ROS. TXNIP-NLRP3 binding
Acute and chronic inflammation, interstitial fibrosis, granuloma formation, and cancer in the lungActivation of NLRP3 inflammasome in macrophages by silica in vitro and in the lung16
Asbestosis, mesotheliomaAsbestos
Phagocytosis. lysosomal disruption. ↑ROS
Acute and chronic inflammation, interstitial fibrosis, granuloma formation, cancer in the lung, and mesothelioma in the pleuraNLRP3−/− mice show reduced lung inflammation upon inhalation of asbestos17
Cancer and metastasis
Tumor and metastasisLow-grade inflammationMCA-induced lung cancer; metastasisAblation of NLRP3 ↓ tumor burden by ↑ NK cell responses18
Anti-tumor vaccinationLow-grade inflammationDendritic cell vaccination against melanomaAblation of NLRP3 ↑vaccination effect by ↓ tumor MDSCs19
  • aReference cited: 1. Aksentijevich et al., 2002; Broderick et al., 2015; Brydges et al., 2013; de Torre-Minguela et al., 2017; Hoffman et al., 2001; Mangan et al., 2018; Masters et al., 2009; Sharif et al., 2019; 2. Coates et al., 2017; Tate et al., 2016; 3. Rodrigues et al., 2021; 4. Ralston et al., 2017; Vandanmagsar et al., 2011; 5. Acosta et al., 2013; Camell et al., 2017; Youm et al., 2013; 6. Besnard et al., 2011; Primiano et al., 2016; 7. Bauer et al., 2010; Cocco et al., 2017; 8. Mridha et al., 2017; Wree et al., 2014; 9. Vande Walle et al., 2014; 10. Coll et al., 2015; Furlan et al., 1999; Huang et al., 2004; Inoue et al., 2012; Matsuki et al., 2006; 11. Goldberg et al., 2017; Martinon et al., 2006; 12. Duewell et al., 2010; Karasawa and Takahashi, 2017; Rajamäki et al., 2010; van der Heijden et al., 2017; 13. Daniels et al., 2016; Dempsey et al., 2017; Halle et al., 2008; Heneka et al., 2013; 14. Codolo et al., 2013; 15. Eisenbarth et al., 2008; Hornung et al., 2008; 16. Cassel et al., 2008; Dostert et al., 2008; Hornung et al., 2008; Peeters et al., 2014; 17. Dostert et al., 2008; 18. Chow et al., 2012; Moossavi et al., 2018; 19. van Deventer et al., 2010.

  • Aβ, amyloid beta; AD, Alzheimer’s disease; αSyn, α-synuclein; CPPD, calcium pyrophosphate dihydrate; DNBS, 2,4-dinitrobenzenesulfonic acid; DSS, dextran sodium sulfate; EAE, experimental autoimmune encephalomyelitis; FCAS, familial cold auto-inflammatory syndrome; IBD, irritable bowel disease; LB, Lewy body; MCA, methylcholanthrene; MDSC, myeloid-derived suppressor cell; MS, multiple sclerosis; MSU, monosodium urate; NAFLD, nonalcoholic fatty liver disease; NK, natural killer; NSAID, nonsteroidal anti-inflammatory drug; PBMC, peripheral blood mononuclear cell; PD, Parkinson’s disease; RA, rheumatoid arthritis; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype.