TABLE 1.

NLRP3 inflammasome-driven disease

Associated Disease	Activator and Mechanism	Disease and Pathologic Feature	Genetic and Pharmacologic Intervention	Refa
Autoinflammatory disease
FCAS MWS NOMID	Gain-of-function mutation in NACHT to disrupt autoinhibition of NLRP3	Fever, 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	1
Infection
IAV	Viral PAMPs and DAMPs IAV M2 protein	Hyperinflammation	MCC950 protects juvenile mice from IAV hyperinflammation	2
SARS-Cov-2	Viral PAMPs and DAMPs	Airway and lung inflammation in mild and severe SARS-Cov-2 patients	Activation of NLRP3 inflammasome in PBMCs and autopsy tissues	3
Metabolic disease and aging
Obesity, type 2 diabetes	Ceramide, fatty acids, and obesity-associated DAMPs	Obesity, low-grade inflammation, fatty liver, insulin resistance	Ablation of NLRP3 ↓ obesity-induced inflammation and insulin resistance	4
Aging	Low-grade inflammation	Systemic low-grade inflammation and multiple aging phenotypes including ↓ lipolysis and ↑ SASP	Ablation of NLRP3 inflammasome protected from multiple, aging-driven phenotypes	5
Common inflammatory/immune pathologic condition
Asthma	Allergic immune signals, nonallergic stimulants	Allergic airway inflammation in mice induced by ovalbumin or house dust mite extract	Ablation of the NLRP3 inflammasome pathway ↓ allergic airway inflammation. MCC950 ↓ airway inflammation	6
IBD	Inflammatory DAMPs	DSS-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	7
NAFLD	Fatty acid, cholesterol	Choline deficient amino acid defined- or methionine/choline-deficient diet induced NAFLD in mice	Ablation of NLRP3 protected mice from induced NAFLD and fibrosis. MCC950 ↓ induced NASH and liver scarring	8
RA	Inflammatory DAMPs	Spontaneous erosive polyarthritis in A20(myol-KO) mice	Ablation of NLRP3 protected against rheumatoid arthritis-associated inflammation and cartilage destruction	9
MS, EAE	DAMPs	Autoimmune encephalomyelitis	Ablation of NLRP3 led to resistance to EAE. MCC950 ↓ the severity of EAE	10
Endogenous particulates-associated pathology
Gout and pseudogout	MSU 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	11
Atherosclerosis	Cholesterol crystal Phagocytosis and lysosomal disruption	Diet- and genetic-induced atherosclerosis; low-level inflammation	Ablation of NLRP3 and other genes ↓ atherosclerotic lesions in mice. MCC950 ↓ atherosclerotic lesions	12
AD	Aβ 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	13
PD	αSyn 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 fibrils	14
Exogenous particulates-associated pathology
Immunization	Aluminum	Phagocytosis and lysosome disruption	Enhancing immunization effect as immunization adjuvant	15
Silicosis, lung cancer	Crystalline silica Phagocytosis. lysosomal disruption. ↑ROS. TXNIP-NLRP3 binding	Acute and chronic inflammation, interstitial fibrosis, granuloma formation, and cancer in the lung	Activation of NLRP3 inflammasome in macrophages by silica in vitro and in the lung	16
Asbestosis, mesothelioma	Asbestos Phagocytosis. lysosomal disruption. ↑ROS	Acute and chronic inflammation, interstitial fibrosis, granuloma formation, cancer in the lung, and mesothelioma in the pleura	NLRP3−/− mice show reduced lung inflammation upon inhalation of asbestos	17
Cancer and metastasis
Tumor and metastasis	Low-grade inflammation	MCA-induced lung cancer; metastasis	Ablation of NLRP3 ↓ tumor burden by ↑ NK cell responses	18
Anti-tumor vaccination	Low-grade inflammation	Dendritic cell vaccination against melanoma	Ablation of NLRP3 ↑vaccination effect by ↓ tumor MDSCs	19

^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.