[KSCI] Korea Science Citation Index Service

http://dx.doi.org/10.14348/molcells.2014.0104

Inflammasomes: Molecular Regulation and Implications for Metabolic and Cognitive Diseases

Choi, Alexander J.S. (Center for Sleep Medicine, Department of Pulmonary, Critical Care, and Sleep Medicine, Tufts University School of Medicine)
Ryter, Stefan W. (Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College)

Abstract

Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multiprotein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)- $1{\beta}$ and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF- ${\kappa}B$ -dependent priming signal. Following exposure to extracellular ATP, stimulation of the P2X purinoreceptor-7 ( $P2X_7R$ ), which results in $K^+$ efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and /or mitochondria-dependent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we discuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer's disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.

Keywords

cognitive disease; diabetes; inflammasome; inflammation; metabolism; obesity;

Citations & Related Records

Reference

1	Wang, L., Zhai, Y.Q., Xu, L.L., Qiao, C., Sun, X.L., Ding, J.H., Lu, M., and Hu, G. (2014b). Metabolic inflammation exacerbates dopaminergic neuronal degeneration in response to acute MPTP challenge in type 2 diabetes mice. Exp. Neurol. 251, 22-29. DOI ScienceOn
2	Warner-Schmidt, J.L., Vanover, K.E., Chen, E.Y., Marshall, J.J., and Greengard, P. (2011). Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc. Natl. Acad. Sci. USA 108, 9262-9267. DOI ScienceOn
3	Wellen, K.E., and Hotamisligil, G.S. (2005). Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111-1119. DOI
4	Wen, H., Gris, D., Lei, Y., Jha, S., Zhang, L., Huang, M.T., Brickey, W.J., and Ting, J.P. (2011). Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408-415. DOI ScienceOn
5	World Health Organization. (2002). The world health report 2002: Reducing risks, promoting healthy life. Geneva WHO 1-167.
6	World Health Organization. (2011). Global status report on noncommunicable diseases 2010. Geneva WHO 1-162.
7	Zhang, Y., Liu, L., Peng, Y.L., Liu, Y.Z., Wu, T.Y., Shen, X.L., Zhou, J.R., Sun, D.Y., Huang, A.J., Wang, X., et al. (2013). Involvement of inflammasome activation in lipopolysaccharide-induced mice depressive-like behaviors. CNS Neurosci. Ther. 20, 119-124.
8	Zhou, R., Tardivel, A., Thorens, B., Choi, I., and Tschopp, J. (2010). Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136-140. DOI ScienceOn
9	Stienestra, R., Joosten, L.A., Koenen, T., van Tits, B., van Diepen, J.A., van den Berg, S.A., Rensen, P.C., Voshol, P.J., Fantuzzi, G., Hijmans, A., et al. (2010). The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Metabolism 12, 593-605.
10	Stienestra, R., van Diepen, J.A., Tack, C.J., Zaki, M.H., van de Veerdonk, F.L., Perera, D., Neale, G.A., Hooiveld, G.J., Hijmans, A., Vroegrijk, I., et al. (2011). Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl. Acad. Sci. USA 108, 15324-15329. DOI ScienceOn
11	Sun, S., Xia, S., Ji, Y., Kersten, S., and Qi, L. (2012). The ATP-P2 x 7 signaling axis is dispensable for obesity-associated inflammasome activation in adipose tissue. Diabetes 61, 1471-1478. DOI
12	Wang, H., Capell, W., Yoon, J.H., Faubel, S., and Eckel, R.H. (2014a). Obesity development in caspase-1-deficient mice. Int. J. Obes. (Lond) 38, 152-155. DOI ScienceOn
13	Trnka, J., Blaikie, F.H., Logan, A., Smith, R.A., and Murphy, M.P. (2009). Antioxidant properties of MitoTEMPOL and its hydroxylamine. Free Radic Res. 43, 4-12. DOI ScienceOn
14	Vandanmagsar, B., Youm, Y.H., Ravussin, A., Galgani, J.E., Stadler, K., Mynatt, R.L., Ravussin, E., Stephens, J.M., and Dixit, V.D. (2011). The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179-188. DOI ScienceOn
15	van Diepen, J.A., Stienstra, R., Vroegrijk, I.O., van den Berg, S.A., Salvatori, D., Hooiveld, G.J., Kersten, S., Tack, C.J., Netea, M.G., Smit, J.W., et al. (2013). Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion. J. Lipid Res. 54, 448-456. DOI
16	Saijo, K., Winner, B., Carson, C.T., Collier, J.G., Boyer, L., Rosenfeld, M.G., Gage, F.H., and Glass, C.K. (2009). A Nurr1/CoR EST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137, 47-59. DOI ScienceOn
17	Sautin, Y.Y., Nakagawa, T., Zharikov, S., and Johnson, R.J. (2007). Adverse effects of the classical antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am. J. Physiol. Cell Physiol. 293, C584-C596 DOI ScienceOn
18	Schroder, K., and Tschopp, J. (2010). The inflammasomes. Cell 140, 821-832. DOI ScienceOn
19	Schroder, K., Zhou, R., and Tschopp, J. (2010). The NLRP3 inflammasome: a sensor for metabolic danger? Science 327, 296-300. DOI ScienceOn
20	Scott, P., Ma, H., Viriyakosol, S., Terkeltaub, R., and Liu-Bryan, R. (2006). Engagement of CD14 mediates the inflammatory potential of monosodium urate crystals. J. Immunol. 177, 6370-6378. DOI
21	Shoelson, S.E., Lee, J., and Goldfine, A.B. (2006). Inflammation and insulin resistance. J. Clin. Invest. 116, 1793-1801. DOI ScienceOn
22	Solini, A., Menini, S., Rossi, C., Ricci, C., Santini, E., Blasetti Fantauzzi, C., Iacobini, C., and Pugliese, G. (2013). The purinergic 2X7 receptor participates in renal inflammation and injury induced by high-fat diet: possible role of NLRP3 inflammasome activation. J. Pathol. 231, 342-353. DOI
23	Nakahira, K., Haspel, J.A., Rathinam, V.A., Lee, S.J., Dolinay, T., Lam, H.C., Englert, J.A., Rabinovitch, M., Cernadas, M., Kim, H.P., et al. (2011). Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222-230.
24	Parvathenani, L.K., Tertyshnikova, S., Greco, C.R., Roberts, S.B., Robertson, B., and Posmantur, R. (2003). P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease. J. Biol. Chem. 278, 13309-13317. DOI ScienceOn
25	Pelegrin, P., and Surprenant, A. (2006). Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J. 25, 5071-5082. DOI ScienceOn
26	Pelegrin, P., and Surprenant, A. (2007). Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptakeindependent pathway. J. Biol. Chem. 282, 2386-2394. DOI ScienceOn
27	Petrilli, V., Papin, S., Dostert, C., Mayor, A., Martinon, F., and Tschopp, J. (2007). Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583-1689. DOI ScienceOn
28	Qu, Y., Misaghi, S., Newton, K., Gilmour, L.L., Louie, S., Cupp, J.E., Dubyak, G.R., Hackos, D., and Dixit, V.M. (2011). Pannexin-1 is required for ATP release during apoptosis but not for inflammasome activation. J. Immunol. 186, 6553-6561. DOI
29	Poyet, J.L., Srinivasula, S.M., Tnani, M., Razmara, M., Fernandes-Alnemri, T., and Alnemri, E.S. (2001). Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J. Biol. Chem. 276, 28309-28313. DOI ScienceOn
30	Qu, Y., Misaghi, S., Newton, K., Gilmour, L.L., Louie, S., Cupp, J.E., Dubyak, G.R., Hackos, D., and Dixit, V.M. (2006). Pannexin-1 is required for ATP release during apoptosis but not for inflammasome activation. J. Immunol. 186, 6553-6561.
31	Martinon, F., Petrilli, V., Mayor, A., Tardivel, A., and Tschopp, J. (2006). Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237-241. DOI ScienceOn
32	Martinon, F., Mayor, A., and Tschopp, J. (2009). The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229-265. DOI ScienceOn
33	Masters, S.L., Dunne, A., Subramanian, S.L., Hull, R.L., Tannahill, G.M., Sharp, F.A., Becker, C., Franchi, L., Yoshihara, E., Chen, Z., et al. (2010). Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1b in type 2 diabetes. Nat. Immunol. 11, 897-904. DOI ScienceOn
34	McGeer, P.L., Itagaki, S., Tago, H., and McGeer, E.G. (1987). Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLADR. Neurosci. Lett. 79, 195-200. DOI ScienceOn
35	Menu, P., and Vince, J.E. (2011). The NLRP3 inflammasome in health and disease: the good, the bad and the ugly. Clin. Exp. Immunol. 166, 1-15. DOI ScienceOn
36	Leemans, J.C., Cassel, S.L., and Sutterwala, F.S. (2011). Sensing damage by the NLRP3 inflammasome. Immunol. Rev. 243, 152-162. DOI ScienceOn
37	Mraz, M., Lacinova, Z., Drapalova, J., Haluzikova, D., Horinek, A., Matoulek, M., Trachta, P., Kavalkova, P., Svacina, S., and Haluzik, M. (2011). The effect of verylow- calorie diet on mRNA expression of inflammation-related genes in subcutaneous adipose tissue and peripheral monocytes of obese patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 96, E606-613. DOI
38	Lamkanfi, M., Mueller, J.L., Vitari, A.C., Misaghi, S., Fedorova, A., Deshayes, K., Lee, W.P., Hoffman, H.M., and Dixit, V.M. (2009). Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J. Cell Biol. 187, 61-70. DOI ScienceOn
39	Latz, E., Xiao, T.S., and Stutz, A. (2013). Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397-411. DOI ScienceOn
40	Liu, Y., Xiao, Y., and Li, Z. (2011). P2X7 receptor positively regulates MyD88-dependent NF-kB activation. Cytokine 55, 229-236. DOI ScienceOn
41	Lu, M., Sun, X.L., Qiao, C., Liu, Y., Ding, J.H., and Hu, G. (2014). Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation. Neurobiol. Aging 35, 421-430. DOI ScienceOn
42	Ludlow, L.E., Johnstone, R.W., and Clarke, C.J. (2005). The HIN-200 family: more than interferon-inducible genes? Exp. Cell Res. 308, 1-17. DOI ScienceOn
43	Maes, M., Bosmans, E., Meltzer, H.Y., Scharpe, S., and Suy, E. (1993). Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? Am. J. Psychiatry 150, 1189-1193. DOI ScienceOn
44	Jankowsky, J.L., Slunt, H.H., Ratovitski, T., Jenkins, N.A., Copeland, N.G., and Borchelt, D.R. (2001). Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol. Eng. 17, 157-165. DOI ScienceOn
45	Mariathasan, S., Newton, K., Monack, D.M., Vucic, D., French, D.M., Lee, W.P., Roose-Girma, M., Erickson, S., and Dixit, V.M. (2004). Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213-218. DOI ScienceOn
46	Martinon, F., Burns, K., and Tschopp, J. (2002). The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL- $1{\beta}$ . Mol. Cell 10, 417-426. DOI ScienceOn
47	Iwata, M., Ota, K.T., and Duman, R.S. (2013). The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav. Immun. 31, 105-114. DOI ScienceOn
48	Kahn, S.E., Hull, R.L., and Utzschneider, K.M.. (2006). Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840-846. DOI ScienceOn
49	Kanneganti, T.D., Lamkanfi, M., Kim, Y.G., Chen, G., Park, J.H., Franchi, L., Vandenabeele, P., and Nunez, G. (2007). Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26, 433-443. DOI ScienceOn
50	Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K.R., Rush, A.J., Walters, E.E., Wang, P.S., and National Comorbidity Survey Replication (2003). The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). J. Am. Med. Assoc. 289, 3095-3105. DOI ScienceOn
51	Koo, J.W., and Duman, R.S. (2008). IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl. Acad. Sci. USA 105, 751-756. DOI ScienceOn
52	Hentze, H., Lin, X.Y., Choi, M.S., and Porter, A.G. (2003). Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin. Cell Death Differ. 10, 956-968. DOI ScienceOn
53	Korcok, J., Raimundo, L.N., Ke, H.Z., Sims, S.M., and Dixon, S.J. (2004). Extracellular nucleotides act through P2X7 receptors to activate NF-kB in osteoclasts. J. Bone Miner. Res. 19, 642-651. DOI ScienceOn
54	Kotas, M.E., Jurczak, M.J., Annicelli, C., Gillum, M.P., Cline, G.W., Shulman, G.I., and Medzhitov, R. (2013). Role of caspase-1 in regulation of triglyceride metabolism. Proc. Natl. Acad. Sci. USA 110, 4810-4815. DOI ScienceOn
55	Heneka, M.T., Kummer, M.P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, TC., et al. (2013). NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674-678.
56	Hiscott, J., Marois, J., Garoufalis, J., D'Addario, M., Roulston, A., Kwan, I., Pepin, N., Lacoste, J., Nguyen, H., Bensi, G., et al. (1993). Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol. Cell. Biol. 13, 6231-6240.
57	Hook, V.Y., Kindy, M., and Hook, G. (2008). Inhibitors of cathepsin B Improve memory and reduce b-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, b-secretase site of the amyloid precursor protein. J. Biol. Chem. 283, 7745-7753. DOI ScienceOn
58	Hornung, V., Bauernfeind, F., Halle, A., Samstad, E.O., Kono, H., Rock, K.L., Fitzgerald, K.A., and Latz, E. (2008). Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847-856. DOI ScienceOn
59	Itagaki, S., McGeer, P.L., Akiyama, H., Zhu, S., and Selkoe, D. (1989). Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J. Neuroimmunol. 24, 173-182. DOI ScienceOn
60	Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D.R., Latz, E., and Fitzgerald, K.A. (2009). AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514-518. DOI ScienceOn
61	Finucane, M.M., Stevens, G.A., Cowan, M.J., Danaei, G., Lin, J.K., Paciorek, C.J., Singh, G.M., Gutierrez, H.R., Lu, Y., Bahalim, A.N., et al. (2011). National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 337, 557-567.
62	Franchi, L., Eigenbrod, T., and Nunez, G. (2009). Cutting edge: TNF-a mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J. Immunol. 183, 792-796. DOI ScienceOn
63	Fujihara, M., Muroi, M., Tanamoto, K., Suzuki, T., Azuma, H., and Ikeda, H. (2003). Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex. Pharmacol. Ther. 100, 171-194. DOI ScienceOn
64	Glinsky, G.V. (2008). SNP-guided microRNA maps (MirMaps) of 16 common human disorders identify a clinically accessible therapy reversing transcriptional aberrations of nuclear import and inflammasome pathways. Cell Cycle 7, 3564-3576. DOI
65	Guarda, G., Zenger, M., Yazdi, A.S., Schroder, K., Ferrero, I., Menu, P., Tardivel, A., Mattmann, C., and Tschopp, J. (2011). Differential expression of NLRP3 among hematopoietic cells. J. Immunol. 186, 2529-2534. DOI
66	Donath, M.Y., and Shoelson, S.E. (2011). Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98-107. DOI ScienceOn
67	Halle, A., Hornung, V., Petzold, G.C., Stewart, C.R., Monks, B.G., Reinheckel, T., Fitzgerald, K.A., Latz, E., Moore, K.J., and Golenbock, D.T. (2008). The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 9, 857-865. DOI ScienceOn
68	Heid, M.E., Keyel, P.A., Kamga, C., Shiva, S., Watkins, S.C., and Salter, R.D. (2013). Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J. Immunol. 191, 5230-5238. DOI ScienceOn
69	Devi, T.S., Lee, I., Huttemann, M., Kumar, A., Nantwi, K.D., and Singh, L.P. (2012). TXNIP links innate host defense mechanisms to oxidative stress and inflammation in retinal Muller glia under chronic hyperglycemia: implications for diabetic retinopathy. Exp. Diabetes Res. 2012, 438238.
70	Dostert, C., Petrilli, V., Van Bruggen, R., Steele, C., Mossman, B.T., and Tschopp J. (2008). Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674-677. DOI ScienceOn
71	Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E.K., and Lanctot, K.L. (2010). A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446-457. DOI ScienceOn
72	Eizirik, D.L., Sammeth, M, Bouckenooghe, T., Bottu, G., Sisino, G., Igoillo-Esteve, M., Ortis, F., Santin, I., Colli, M.L., Barthson, J., et al. (2012). The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet. 8, e1002552. DOI ScienceOn
73	Emanuela, F., Grazia, M., Marco de, R., Maria Paola, L., Giorgio, F., and Marco, B. (2012). Inflammation as a link between obesity and metabolic syndrome. J. Nutr. Metab. 2012, 476380.
74	Balistreri, C.R., Colonna-Romano, G., Lio, D., Candore, G., and Caruso, C. (2009). TLR4 polymorphisms and ageing: implications for the pathophysiology of age-related diseases. J. Clin. Immunol. 29, 406-415. DOI ScienceOn
75	Faustin, B., Lartigue, L., Bruey, J.M., Luciano, F., Sergienko, E., Bailly-Maitre, B., Volkmann, N., Hanein, D., Rouiller, I., and Reed, J.C. (2007). Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol. Cell 25, 713-724. DOI ScienceOn
76	Feve, B., and Bastard, J.P. (2009). The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 5, 305-311 DOI ScienceOn
77	Allen, I.C., Scull, M.A., Moore, C.B., Holl, E.K., McElvania-TeKippe, E., Taxman, D.J., Guthrie E.H., Pickles, R.J., and Ting, J.P. (2009). The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 30, 556-565. DOI ScienceOn
78	Bauernfeind, F.G., Horvath, G., Stutz, A., Alnemri, E.S., MacDonald, K., Speert, D., Fernandes-Alnemri, T., Wu, J., Monks, B.G., Fitzgerald, K.A., et al. (2009). Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787-791. DOI ScienceOn
79	Chatterjee, S., Rana, R., Corbett, J., Kadiiska, M.B., Goldstein, J., and Mason, R.P. (2012). P2X7 receptor-NADPH oxidase axis mediates protein radical formation and Kupffer cell activation in carbon tetrachloride-mediated steatohepatitis in obese mice. Free Radic. Biol. Med. 52, 1666-1679. DOI ScienceOn
80	Davis, B.K., Wen, H., and Ting, J.P. (2011). The Inflammasome NLRs in immunity, inflammation, and associated diseases. Ann. Rev. Immun 29, 707-735. DOI ScienceOn
81	Mandrup-Poulsen, T., Pickersgill, L., and Donath, M.Y. (2010). Blockade of interleukin 1 in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 6, 158-166. DOI ScienceOn
82	Raison, C.L., and Miller, A.H. (2013). Malaise, melancholia and madness: The evolutionary legacy of an inflammatory bias. Brain Behav. Immun. 13, 467-475.
83	Skeldon, A.M., Faraj, M., and Saleh, M. (2014). Caspases and inflammasomes in metabolic inflammation. Immunol. Cell Biol. 92, 304-313. DOI ScienceOn
84	Meyer-Luehmann, M., Spires-Jones, T.L., Prada, C., Garcia-Alloza, M., de Calignon, A., Rozkalne, A., Koenigsknecht-Talboo, J., Holtzman, D.M., Bacskai, B.J., and Hyman, B.T. (2008). Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451, 720-724. DOI ScienceOn
85	Glass, C.K., Saijo, K., Winner, B., Marchetto, M.C., and Gage, F.H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-934. DOI ScienceOn
86	Alcocer-Gomez, E., de Miguel, M., Casas-Barquero, N., Nunez-Vasco, J., Sanchez-Alcazar, J.A., Fernandez-Rodriguez, A., and Cordero, M.D. (2013). NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav. Immun. 36, 111-117.

Reference

1	Yusr M.I. Kazem. (2016) Asian Journal of Clinical Nutrition High Sensitivity C-reactive Protein may be used as a Marker for Cognitive Impairment in Obese Egyptian Middle Age Females / 9 (1) , 17
	Jing Qiu. (2016) International Immunopharmacology The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling / 40 , 492
6	L. E. Felley. (2016) The Journal of Immunology Human Invariant NKT Cells Induce IL-1β Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway / 197 (6) , 2455
2	Mithilesh Kumar Jha. (2015) Expert Opinion on Therapeutic Patents Innate immune proteins as biomarkers for CNS injury: critical evaluation (WO2013119673 A1) / 25 (2) , 241
1	Shu-cong Zheng. (2015) Journal of Inflammation Role of the NLRP3 inflammasome in the transient release of IL-1β induced by monosodium urate crystals in human fibroblast-like synoviocytes / 12 (1)
1	Ying Li. (2015) Toxicology and Applied Pharmacology Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK / 286 (1) , 53
	Yan Zhao. (2015) Journal of Ethnopharmacology Astragaloside IV and cycloastragenol are equally effective in inhibition of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in the endothelium / 169 , 210
6	Fei Song. (2016) The Journals of Gerontology Series A: Biological Sciences and Medical Sciences The Expression Changes of Inflammasomes in the Aging Rat Kidneys / 71 (6) , 747
1	Maria Lombardi. (2017) Scientific Reports P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels / 7 (1)
5	LAN ZENG. (2014) International Journal of Oncology Naringin inhibits growth and induces apoptosis by a mechanism dependent on reduced activation of NF-κB/COX-2-caspase-1 pathway in HeLa cervical cancer cells / 45 (5) , 1929
	Fernanda N. Kaufmann. (2017) Brain, Behavior, and Immunity NLRP3 inflammasome-driven pathways in depression: Clinical and preclinical findings / 64 , 367
6	Maghsoud Peeri. (2015) Medical Hypotheses Protective effects of exercise in metabolic disorders are mediated by inhibition of mitochondrial-derived sterile inflammation / 85 (6) , 707
	Yongfeng Zhang. (2016) Mediators of Inflammation NLRP3 Inflammasome Plays an Important Role in the Pathogenesis of Collagen-Induced Arthritis / 2016 , 1
9	Marijke De Bock. (2017) Neurochemical Research Connexin Channels at the Glio-Vascular Interface: Gatekeepers of the Brain / 42 (9) , 2519
	Yujun Wang. (2016) Behavioural Brain Research Exercise amelioration of depression-like behavior in OVX mice is associated with suppression of NLRP3 inflammasome activation in hippocampus / 307 , 18
9	Ren-Hong Du. (2016) International Journal of Neuropsychopharmacology Fluoxetine Inhibits NLRP3 Inflammasome Activation: Implication in Depression / 19 (9) , pyw037
	Shayan Amiri. (2017) Neuroscience Streptozotocin induced oxidative stress, innate immune system responses and behavioral abnormalities in male mice / 340 , 373
4	Mohammad Momeni. (2016) Nordic Journal of Psychiatry ASC provides a potential link between depression and inflammatory disorders: A clinical study of depressed Iranian medical students / 70 (4) , 280
	Xiaoshan Xu. (2018) European Journal of Nutrition Mangiferin suppresses endoplasmic reticulum stress in perivascular adipose tissue and prevents insulin resistance in the endothelium /
	Yongjun Xu. (2016) Brain, Behavior, and Immunity NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice / 56 , 175
	Stephanie Reikine. (2014) Frontiers in Immunology Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5 / 5
1	Herbert Zimmermann. (2016) Purinergic Signalling Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release / 12 (1) , 25
9	Marc Fakhoury. (2016) Journal of Neurology Immune-mediated processes in neurodegeneration: where do we stand? / 263 (9) , 1683
14	Y H Lee. (2016) Lupus Association between functional NLRP3 polymorphisms and susceptibility to autoimmune and inflammatory diseases: a meta-analysis / 25 (14) , 1558
1	Dae Wui Yoon. (2017) Sleep Medicine Research Sleep Fragmentation Induces Activation of NOD-Like Receptor Protein-3 Inflammasome in Rat Hippocampus / 8 (1) , 26
	Lianjin Weng. (2016) European Journal of Pharmacology Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice / 774 , 50
	Letteria Minutoli. (2016) Oxidative Medicine and Cellular Longevity ROS-Mediated NLRP3 Inflammasome Activation in Brain, Heart, Kidney, and Testis Ischemia/Reperfusion Injury / 2016 , 1
	Xiaoqin Huang. (2017) Frontiers in Molecular Neuroscience Depression and Chronic Liver Diseases: Are There Shared Underlying Mechanisms? / 10
1	Jingya Yu. (2015) International Immunopharmacology Paeoniflorin down-regulates ATP-induced inflammatory cytokine production and P2X7R expression on peripheral blood mononuclear cells from patients with primary Sjögren's syndrome / 28 (1) , 115
4	Philippe Leff-Gelman. (2016) Neuroscience Bulletin The Immune System and the Role of Inflammation in Perinatal Depression / 32 (4) , 398
3	Chang-Min Lee. (2016) International Journal of Molecular Medicine Benzyl isothiocyanate inhibits inflammasome activation in E. coli LPS-stimulated BV2 cells / 38 (3) , 912
	Yi Li. (2015) Pharmacological Research Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner / 99 , 101
	Hui Song. (2016) Nature Communications The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3 / 7 , 13727
3	Junna Song. (2015) Metabolism Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells / 64 (3) , 428
	Min Li. (2017) Neuroscience Letters Astragaloside IV attenuates cognitive impairments induced by transient cerebral ischemia and reperfusion in mice via anti-inflammatory mechanisms / 639 , 114
	Ruipeng Li. (2015) Neuroscience Letters The effects of apigenin on lipopolysaccharide-induced depressive-like behavior in mice / 594 , 17
1	Ingar Olsen. (2016) Journal of Alzheimer's Disease Inflammasome Involvement in Alzheimer’s Disease / 54 (1) , 45
2	(2018) Journal of Neuroendocrinology Brain inflammasomes in stroke and depressive disorders: Regulation by oestrogen / 30 (2) , e12482
3	(2018) Journal of Cellular and Molecular Medicine ROS- and P2X7R-mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose / 22 (3) , 1816
1664-3224	(2018) Frontiers in Immunology NLR-Dependent Regulation of Inflammation in Multiple Sclerosis / 8 (1664-3224)
50	(2018) Journal of agricultural and food chemistry Inhibition of P2X7R-NLRP3 Inflammasome Activation by <I>Pleurotus citrinopileatus</I>: A Possible Protective Role in Alcoholic Hepatosteatosis / 66 (50) , 13183
3	(2018) Cell Death & Disease Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation / 9 (3)
1530-0307	(2018) Laboratory Investigation The role of Ca2+ in acid-sensing ion channel 1a-mediated chondrocyte pyroptosis in rat adjuvant arthritis / (1530-0307)
1	(2018) Arthritis Research & Therapy Recombinant human proteoglycan-4 reduces phagocytosis of urate crystals and downstream nuclear factor kappa B and inflammasome activation and production of cytokines and chemokines in human and murine macrophages / 20 (1)
1662-5102	(2019) Frontiers in Cellular Neuroscience The Potential Role of the NLRP3 Inflammasome Activation as a Link Between Mitochondria ROS Generation and Neuroinflammation in Postoperative Cognitive Dysfunction / 13 (1662-5102)
None	(2017) The Canadian journal of infectious diseases & medical microbiology Inflammasomes in <I>Mycobacterium tuberculosis</I> -Driven Immunity / 2017 (None) , 2309478
6	(2014) The journal of immunology : official journal of the American Association of Immunologists The Inflammatory Bowel Disease–Associated Autophagy Gene <I>Atg16L1T300A</I> Acts as a Dominant Negative Variant in Mice / 198 (6) , 2457
None	(2014) Scientific reports Soluble Uric Acid Activates the NLRP3 Inflammasome / 7 (None) , 39884
4	(2014) Archives of medical science : AMS Pretreatment with obestatin inhibits the development of acetic acid-induced colitis in rats / 14 (4) , 920
12	(2018) Journal of medicinal chemistry Structural Insights of Benzenesulfonamide Analogues as NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization / 61 (12) , 5412
None	(2014) Frontiers in oncology The Roles of TIF1γ in Cancer / 9 (None) , 979
None	(2014) Frontiers in molecular neuroscience Glucocorticoid-Driven NLRP3 Inflammasome Activation in Hippocampal Microglia Mediates Chronic Stress-Induced Depressive-Like Behaviors / 12 (None) , 210
None	(2019) Toxicology letters Involvement of NLRP3 inflammasome in methamphetamine-induced microglial activation through miR-143/PUMA axis / 301 (None) , 53
2	(2014) International journal of molecular medicine Ginsenoside Rg1 protects against H <SUB>2</SUB> O <SUB>2</SUB> -induced neuronal damage due to inhibition of the NLRP1 inflammasome signalling pathway in hippocampal neurons <I>in vitro</I> / 43 (2) , 717
3	(2014) Molecular cell The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy / 73 (3) , 429
2	(2014) Heart and mind The depressed heart / 3 (2) , 35
8	(2014) Molecular neurobiology Role of Chronic Administration of Antidepressant Drugs in the Prenatal Stress-Evoked Inflammatory Response in the Brain of Adult Offspring Rats: Involvement of the NLRP3 Inflammasome-Related Pathway / 56 (8) , 5365
21	(2019) Journal of medicinal chemistry Discovery of Second-Generation NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization / 62 (21) , 9718
1	(2014) Cell metabolism The World Goes Bats: Living Longer and Tolerating Viruses / 32 (1) , 31
10	(2020) Nucleosides, nucleotides & nucleic acids Toll-Like receptor 4 (TLR4) polymorphism rs2149356 and risk of gout in a Spanish cohort / 39 (10) , 1424
4	(2014) Applied in vitro toxicology Evaluation of Potential Risks to Human Health and Ecosystems During Exposure to Discarded Laboratory Chemical Mixtures by <I>In Vitro</I> Multimodel Approach / 6 (4) , 131
2	(2014) Medicinal chemistry research Structural insights of sulfonamide-based NLRP3 inflammasome inhibitors: design, synthesis, and biological characterization / 30 (2) , 473
3	(2014) Marine drugs Ecklonia cava Attenuates PM2.5-Induced Cognitive Decline through Mitochondrial Activation and Anti-Inflammatory Effect / 19 (3) , 131
no.pb	(2021) International immunopharmacology RGFP966 is protective against lipopolysaccharide-induced depressive-like behaviors in mice by inhibiting neuroinflammation and microglial activation / 101 (no.pb) , 108259
1	(2021) Behavioral and brain functions : BBF NLRP1 inflammasome involves in learning and memory impairments and neuronal damages during aging process in mice / 17 (1) , 11