Irritative voiding symptoms (e.g. increased frequency and urgency) occur in many common pathologic conditions such as urinary tract infections and bladder outlet obstruction, and these conditions are well-established to have underlying inflammation that directly triggers these symptoms. However, it remains unclear as to how such diverse stimuli individually generate a common inflammatory process. Jürg Tschopp provided substantial insight into this conundrum when, working with extracts from THP-1 cells, he reported the existence of the inflammasome. He described it as a structure that senses multiple diverse signals from intracellular/extracellular sources and pathogens and triggers inflammation by the maturation and release of the pro-inflammatory cytokines interleukin-1β and interleukin-18. Recently, many of these sensors were found in the bladder and the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, has been shown to be a central mediator of inflammation in several urological diseases. In this review, we introduce the nucleotide-binding domain, leucine-rich-containing family, pyrin domaincontaining-3 inflammasome, highlight its emerging role in several common urologic conditions, and speculate on the potential involvement of other inflammasomes in bladder pathology.

Keywords:
Inflammasomes, NLRP3, Bladder outlet obstruction, Urinary tract infection, Urothelial carcinoma, Bladder cancer
1.
Martinon F, Burns K, Tschopp J: The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002;10: 417-426.
2.
Purves JT, Hughes FM Jr: Inflammasomes in the urinary tract: a disease-based review. Am J Physiol Renal Physiol 2016;311:F653-F662.
3.
Hamilton C, Tan L, Miethke T, Anand PK: Immunity to uropathogens: the emerging roles of inflammasomes. Nat Rev Urol 2017; 14:284-295.
4.
Mogensen TH: Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 2009;22:240-273.
5.
Lamkanfi M, Dixit VM: Modulation of inflammasome pathways by bacterial and viral pathogens. J Immunol 2011;187:597-602.
6.
Takeuchi O, Akira S: Pattern recognition receptors and inflammation. Cell 2010;140: 805-820.
7.
Lappas M: NOD1 and NOD2 regulate proinflammatory and prolabor mediators in human fetal membranes and myometrium via nuclear factor-kappa B. Biol Reproduct 2013; 89:14.
8.
Wilmanski JM, Petnicki-Ocwieja T, Kobayashi KS: NLR proteins: integral members of innate immunity and mediators of inflammatory diseases. J Leukoc Biol 2008;83:13- 30.
9.
Kayagaki N, Stowe IB, Lee BL, O'Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM: Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015;526:666-671.
10.
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F: Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015;526:660-665.
11.
Lamkanfi M, Dixit VM: Mechanisms and functions of inflammasomes. Cell 2014;157: 1013-1022.
12.
Fink SL, Cookson BT: Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol 2006;8:1812-1825.
13.
Poeck H, Bscheider M, Gross O, Finger K, Roth S, Rebsamen M, Hannesschläger N, Schlee M, Rothenfusser S, Barchet W, Kato H, Akira S, Inoue S, Endres S, Peschel C, Hartmann G, Hornung V, Ruland J: Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol 2010;11:63-69.
14.
Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA: AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 2009; 458:514-518.
15.
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E: Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 2009;183:787-791.
16.
Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM: Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006;440: 228-232.
17.
Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237-241.
18.
Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, van Bruggen R, Tschopp J: Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J Histochem Cytochem 2007;55: 443-452.
19.
Hughes FM Jr, Turner DP, Todd Purves J: The potential repertoire of the innate immune system in the bladder: expression of pattern recognition receptors in the rat bladder and a rat urothelial cell line (MYP3 cells). Int Urol Nephrol 2015;47:1953-1964.
20.
Guo H, Callaway JB, Ting JP: Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 2015;21: 677-687.
21.
Sutterwala FS, Haasken S, Cassel SL: Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci 2014;1319:82-95.
22.
Wen H, Miao EA, Ting JP: Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 2013;39:432-441.
23.
Gaidt MM, Hornung V: Alternative inflammasome activation enables IL-1beta release from living cells. Curr Opin Immunol 2016; 44:7-13.
24.
He Y, Hara H, Nunez G: Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci 2016;41:1012-1021.
25.
Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F, Robertson AA, Cooper MA, Graf T, Hornung V: Human monocytes engage an alternative inflammasome pathway. Immunity 2016;44:833- 846.
26.
Patel MN, Carroll RG, Galvan-Pena S, Mills EL, Olden R, Triantafilou M, Wolf AI, Bryant CE, Triantafilou K, Masters SL: Inflammasome priming in sterile inflammatory disease. Trends Mol Med 2017;23:165-180.
27.
Franchi L, Eigenbrod T, Nunez G: Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol 2009;183:792-796.
28.
Py BF, Kim MS, Vakifahmetoglu-Norberg H, Yuan J: Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell 2013;49:331-338.
29.
Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES: Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem 2012;287:36617-36622.
30.
Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J: Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 2008; 320:674-677.
31.
Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, Nunez G: K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 2013; 38:1142-1153.
32.
Harijith A, Ebenezer DL, Natarajan V: Reactive oxygen species at the crossroads of inflammasome and inflammation. Front Physiol 2014;5:352.
33.
Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL, Chae JJ: The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 2012;492:123-127.
34.
Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, Horng T: Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci USA 2012;109:11282-11287.
35.
Rossol M, Pierer M, Raulien N, Quandt D, Meusch U, Rothe K, Schubert K, Schöneberg T, Schaefer M, Krügel U, Smajilovic S, Bräuner-Osborne H, Baerwald C, Wagner U: Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors. Nat Commun 2012;3:1329.
36.
Katsnelson MA, Rucker LG, Russo HM, Dubyak GR: K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling. J Immunol 2015;194:3937- 3952.
37.
Franchi L, Kanneganti TD, Dubyak GR, Nunez G: Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. J Biol Chem 2007;282: 18810-18818.
38.
Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J: Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 2007;14:1583-1589.
39.
Bortner CD, Hughes FM Jr, Cidlowski JA: A primary role for K+ and Na+ efflux in the activation of apoptosis. J Biol Chem 1997; 272:32436-32442.
40.
Hughes FM Jr, Bortner CD, Purdy GD, Cidlowski JA: Intracellular K+ suppresses the activation of apoptosis in lymphocytes. J Biol Chem 1997;272:30567-30576.
41.
Bortner CD, Cidlowski JA: Cell shrinkage and monovalent cation fluxes: role in apoptosis. Arch Biochem Biophys 2007;462:176- 188.
42.
He Y, Zeng MY, Yang D, Motro B, Nunez G: NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 2016;530:354-357.
43.
Shi H, Wang Y, Li X, Zhan X, Tang M, Fina M, Su L, Pratt D, Bu CH, Hildebrand S, Lyon S, Scott L, Quan J, Sun Q, Russell J, Arnett S, Jurek P, Chen D, Kravchenko VV, Mathison JC, Moresco EM, Monson NL, Ulevitch RJ, Beutler B: NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat Immunol 2016;17:250-258.
44.
Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang DC, Shao F: Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 2016;535:111- 116.
45.
Sborgi L, Ruhl S, Mulvihill E, Pipercevic J, Heilig R, Stahlberg H, Farady CJ, Müller DJ, Broz P, Hiller S: GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J 2016;35:1766-1778.
46.
Aglietti RA, Estevez A, Gupta A, Ramirez MG, Liu PS, Kayagaki N, Ciferri C, Dixit VM, Dueber EC: GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc Natl Acad Sci USA 2016;113:7858-7863.
47.
Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J, Lee WP, Roose-Girma M, Dixit VM: Non-canonical inflammasome activation targets caspase-11. Nature 2011;479:117-121.
48.
Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F: Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014;514:187-192.
49.
Wang S, Miura M, Jung YK, Zhu H, Li E, Yuan J: Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 1998;92:501-509.
50.
Gross CJ, Mishra R, Schneider KS, Médard G, Wettmarshausen J, Dittlein DC, Shi H, Gorka O, Koenig PA, Fromm S, Magnani G, Ćiković T, Hartjes L, Smollich J, Robertson AAB7, Cooper MA, Schmidt-Supprian M, Schuster M, Schroder K, Broz P, Traidl-Hoffmann C4, Beutler B, Kuster B, Ruland J, Schneider S, Perocchi F, Groß O: K+ efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Immunity 2016;45:761-773.
51.
Hughes FM Jr, Vivar NP, Kennis JG, Pratt-Thomas JD, Lowe DW, Shaner BE, Nietert PJ, Spruill LS, Purves JT: Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation. Am J Physiol Renal physiol 2014;306:F299-308.
52.
Smaldone MC, Vodovotz Y, Tyagi V, Barclay D, Philips BJ, Yoshimura N, Chancellor MB, Tyagi P: Multiplex analysis of urinary cytokine levels in rat model of cyclophosphamide-induced cystitis. Urology 2009;73: 421-426.
53.
Leite CA, Alencar VT, Melo DL, Mota JM, Melo PH, Mourão LT, Wong DV, Magalhães PJ, Santos AA, Brito GA, Lima-Júnior RC, Cunha FQ, Ribeiro RA: Target inhibition of IL-1 receptor prevents Ifosfamide induced hemorrhagic cystitis in mice. J Urol 2015; 194:1777-1786.
54.
Ribeiro RA, Freitas HC, Campos MC, Santos CC, Figueiredo FC, Brito GA, Cunha FQ: Tumor necrosis factor-alpha and interleukin-1beta mediate the production of nitric oxide involved in the pathogenesis of ifosfamide induced hemorrhagic cystitis in mice. J Urol 2002;167:2229-2234.
55.
Batista CK, Brito GA, Souza ML, Leitao BT, Cunha FQ, Ribeiro RA: A model of hemorrhagic cystitis induced with acrolein in mice. Braz J Med Biol Res 2006;39:1475-1481.
56.
Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, Deshayes K, Lee WP, Hoffman HM, Dixit VM: Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol 2009;187:61-70.
57.
Haldar S, Dru C, Choudhury D, Mishra R, Fernandez A, Biondi S, Liu Z, Shimada K, Arditi M, Bhowmick NA: Inflammation and pyroptosis mediate muscle expansion in an interleukin-1beta (IL-1beta)-dependent manner. J Biological Chemistry 2015;290:6574-6583.
58.
Metcalfe PD, Wang J, Jiao H, Huang Y, Hori K, Moore RB, Tredget EE: Bladder outlet obstruction: progression from inflammation to fibrosis. BJU Int 2010;106:1686-1694.
59.
Oka M, Fukui T, Ueda M, Tagaya M, Oyama T, Tanaka M: Suppression of bladder oxidative stress and inflammation by a phytotherapeutic agent in a rat model of partial bladder outlet obstruction. J Urol 2009;182:382-390.
60.
Deveaud CM, Macarak EJ, Kucich U, Ewalt DH, Abrams WR, Howard PS: Molecular analysis of collagens in bladder fibrosis. J Urol 1998;160:1518-1527.
61.
Hughes FM, Govada V, Sexton SJ, Purves J: Fibrosis in the bladder in response to outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1β. Transl Androl Urol 2016;5(Suppl 2):AB279.
62.
Hughes FM Jr, Hill HM, Wood CM, Edmondson AT, Dumas A, Foo WC, Oelsen JM, Rac G, Purves JT: The NLRP3 inflammasome mediates inflammation produced by bladder outlet obstruction. J Urol 2016;195:1598-1605.
63.
Lutolf R, Hughes FM, Purves J: NLRP3/ IL-1β mediates denervation during bladder outlet obstruction in rats. Transl Androl Urol 2016;5(Suppl 2):AB298.
64.
Kanno Y, Mitsui T, Kitta T, Moriya K, Tsukiyama T, Hatakeyama S, Nonomura K: The inflammatory cytokine IL-1beta is involved in bladder remodeling after bladder outlet obstruction in mice. Neurourol Urodyn 2016; 35:3773-3778.
65.
Abderrazak A, Syrovets T, Couchie D, El Hadri K, Friguet B, Simmet T, Rouis M: NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biol 2015;4:296-307.
66.
Yamaguchi O, Nomiya M, Andersson KE: Functional consequences of chronic bladder ischemia. Neurourol Urodyn 2014;33:54-58.
67.
Gombault A, Baron L, Couillin I: ATP release and purinergic signaling in NLRP3 inflammasome activation. Front Immunol 2012;3: 414.
68.
Olsen SM, Stover JD, Nagatomi J: Examining the role of mechanosensitive ion channels in pressure mechanotransduction in rat bladder urothelial cells. Ann Biomed Eng 2011; 39:688-697.
69.
Dunton CL, Hughes FM, Purves J, Nagatomi J: In vitro evaluation of hydrostatic pressure on ATP release and Caspase-1 activation in rat urothelial cells. Transl Androl Urol 1916; 5(Suppl 2):AB276.
70.
Chen S, Peng C, Wei X, Luo D, Lin Y, Yang T, Jin X, Gong L, Li H, Wang K: Simulated physiological stretch increases expression of extracellular matrix proteins in human bladder smooth muscle cells via integrin alpha4/alphav-FAK-ERK1/2 signaling pathway. World J Urology 2017;35:1247-1254.
71.
Dunning-Davies BM, Fry CH, Mansour D, Ferguson DR: The regulation of ATP release from the urothelium by adenosine and transepithelial potential. BJU Int 2013;111:505-513.
72.
Mochizuki T, Sokabe T, Araki I, Fujishita K, Shibasaki K, Uchida K, Naruse K, Koizumi S, Takeda M, Tominaga M: The TRPV4 cation channel mediates stretchevoked Ca2+ influx and ATP release in primary urothelial cell cultures. J Biol Chem 2009;284:21257-21264.
73.
Ochodnicky P, Michel MB, Butter JJ, Seth J, Panicker JN, Michel MC: Bradykinin modulates spontaneous nerve growth factor production and stretch-induced ATP release in human urothelium. Pharmacol Res 2013;70: 147-154.
74.
Young JS, Matharu R, Carew MA, Fry CH: Inhibition of stretching-evoked ATP release from bladder mucosa by anticholinergic agents. BJU Int 2012;110:E397-401.
75.
Moro C, Uchiyama J, Chess-Williams R: Urothelial/lamina propria spontaneous activity and the role of M3 muscarinic receptors in mediating rate responses to stretch and carbachol. Urology 2011;78:1442e9- 15.
76.
Cheng Y, Mansfield KJ, Sandow SL, Sadananda P, Burcher E, Moore KH: Porcine bladder urothelial, myofibroblast, and detrusor muscle cells: characterization and ATP release. Front Pharmacol 2011;2:27.
77.
Ferguson DR, Kennedy I, Burton TJ: ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes-a possible sensory mechanism? J Physiol 1997; 505( Pt 2):503-511.
78.
Beckel JM, Birder LA: Differential expression and function of nicotinic acetylcholine receptors in the urinary bladder epithelium of the rat. J Physiology 2012;590:1465- 1480.
79.
McLatchie LM, Young JS, Fry CH: Regulation of ACh release from guinea pig bladder urothelial cells: potential role in bladder filling sensations. Br J Pharmacol 2014;171: 3394-3403.
80.
Sun Y, Chai TC: Augmented extracellular ATP signaling in bladder urothelial cells from patients with interstitial cystitis. Am J Physiol Cell physiol 2006;290:C27-34.
81.
Bugyei-Twum A, Abadeh A, Thai K, Zhang Y, Mitchell M, Kabir G, Connelly KA: Suppression of NLRP3 inflammasome activation ameliorates chronic kidney disease-induced cardiac fibrosis and diastolic dysfunction. Sci Rep 2016;6:39551.
82.
Sayan M, Mossman BT: The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases. Part Fibre Toxicol 2016;13:51.
83.
Gong W, Mao S, Yu J, Song J, Jia Z, Huang S, Zhang A: NLRP3 deletion protects against renal fibrosis and attenuates mitochondrial abnormality in mouse with 5/6 nephrectomy. Am J Physiol Renal Physiol 2016;310: F1081-1088.
84.
Gasse P, Riteau N, Vacher R, Michel ML, Fautrel A, di Padova F, Fick L, Charron S, Lagente V, Eberl G, Le Bert M, Quesniaux VF, Huaux F, Leite-de-Moraes M, Ryffel B, Couillin I: IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis. PloS One 2011;6: e23185.
85.
Sexton SJ, Hughes FM, Purves JT: Fibrosis in the bladder in response to outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1β. North Carolina Urology Association, Durham, ND 2016.
86.
Harrison SC, Hunnam GR, Farman P, Ferguson DR, Doyle PT: Bladder instability and denervation in patients with bladder outflow obstruction. Br J Urol 1987;60:519-522.
87.
Speakman MJ, Brading AF, Gilpin CJ, Dixon JS, Gilpin SA, Gosling JA: Bladder outflow obstruction-a cause of denervation supersensitivity. J Urol 1987;138:1461- 1466.
88.
de Jongh R, Dambros M, Haenen GR, den Hartog GJ, Bast A, van Kerrebroeck PE, van Koeveringe GA: Partial bladder outlet obstruction reduces the tissue antioxidant capacity and muscle nerve density of the guinea pig bladder. Neurourol Urodyn 2009;28:461-467.
89.
Nyirady P, Thiruchelvam N, Fry CH, Godley ML, Winyard PJ, Peebles DM, Woolf AS, Cuckow PM: Effects of in utero bladder outflow obstruction on fetal sheep detrusor contractility, compliance and innervation. J Urol 2002;168:1615-1620.
90.
Levin RM, Levin SS, Zhao Y, Buttyan R: Cellular and molecular aspects of bladder hypertrophy. Eur Urol 1997;32(Suppl 1):15-21.
91.
Barendrecht MM, Chichester P, Michel MC, Levin RM: Effect of short-term outlet obstruction on rat bladder nerve density and contractility. Auton Autacoid Pharmacol 2007;27:47-53.
92.
Nomiya M, Andersson KE, Yamaguchi O: Chronic bladder ischemia and oxidative stress: new pharmacotherapeutic targets for lower urinary tract symptoms. Int J Urol 2015;22:40-46.
93.
Chughtai B, Lee R, Te A, Kaplan S: Role of inflammation in benign prostatic hyperplasia. Rev Urol 2011;13:147-150.
94.
Kashyap M, Pore S, Wang Z, Gingrich J, Yoshimura N, Tyagi P: Inflammasomes are important mediators of prostatic inflammation associated with BPH. J Inflamm (Lond) 2015;12:37.
95.
Hughes FM Jr, Turner DP, Todd Purves J: The potential repertoire of the innate immune system in the bladder: expression of pattern recognition receptors in the rat bladder and a rat urothelial cell line (MYP3 cells). Int Urol Nephrol 2015;47:1953- 1964.
96.
Agace W, Hedges S, Andersson U, Andersson J, Ceska M, Svanborg C: Selective cytokine production by epithelial cells following exposure to Escherichia coli. Infect Immun 1993;61:602-609.
97.
Foxman B: Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med 2002;113(Suppl 1A):5S-13S.
98.
Hughes FM Jr, Kennis JG, Youssef MN, Lowe DW, Shaner BE, Purves JT: The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome mediates inflammation and voiding dysfunction in a lipopolysaccharide-induced rat model of cystitis. J Clin Cell Immunol 2016;7:396.
99.
Nagamatsu K, Hannan TJ, Guest RL, Kostakioti M, Hadjifrangiskou M, Binkley J, Dodson K, Raivio TL, Hultgren SJ: Dysregulation of Escherichia coli alpha-hemolysin expression alters the course of acute and persistent urinary tract infection. Proc Natl Acad Sci USA 2015;112:E871-880.
100.
Schaale K, Peters KM, Murthy AM, Fritzsche AK, Phan MD, Totsika M, Robertson AA, Nichols KB, Cooper MA, Stacey KJ, Ulett GC, Schroder K, Schembri MA, Sweet MJ: Strain- and host species-specific inflammasome activation, IL-1beta release, and cell death in macrophages infected with uropathogenic Escherichia coli. Mucosal Immunol 2016;9:124-136.
101.
Waldhuber A, Puthia M, Wieser A, Cirl C, Dürr S, Neumann-Pfeifer S, Albrecht S, Römmler F, Müller T, Zheng Y, Schubert S, Groß O, Svanborg C, Miethke T: Uropathogenic Escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation. J Clin Invest 2016;126:2425-2436.
102.
Schubert S, Norenberg D, Clermont O, Magistro G, Wieser A, Romann E, Hoffmann C, Weinert K, Denamur E: Prevalence and phylogenetic history of the TcpC virulence determinant in Escherichia coli. Int J Med Microbiol 2010;300:429-434.
103.
Costa A, Gupta R, Signorino G, Malara A, Cardile F, Biondo C, Midiri A, Galbo R, Trieu-Cuot P, Papasergi S, Teti G, Henneke P, Mancuso G, Golenbock DT, Beninati C: Activation of the NLRP3 inflammasome by group B streptococci. J Immunol 2012;188: 1953-1960.
104.
Ulett GC, Webb RI, Ulett KB, Cui X, Benjamin WH, Crowley M, Schembri MA: Group B Streptococcus (GBS) urinary tract infection involves binding of GBS to bladder uroepithelium and potent but GBS-specific induction of interleukin 1alpha. J Infect Dis 2010;201:866-870.
105.
Gupta R, Ghosh S, Monks B, DeOliveira RB, Tzeng TC, Kalantari P, Nandy A, Bhattacharjee B, Chan J, Ferreira F, Rathinam V, Sharma S, Lien E, Silverman N, Fitzgerald K, Firon A, Trieu-Cuot P, Henneke P, Golenbock DT: RNA and beta-hemolysin of group B Streptococcus induce interleukin-1beta (IL-1beta) by activating NLRP3 inflammasomes in mouse macrophages. J Biol Chem 2014;289:13701-13705.
106.
Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Núñez G: Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 2006;440:233-236.
107.
Franchi L, Eigenbrod T, Munoz-Planillo R, Muñoz-Planillo R, Ozkurede U, Kim YG, Arindam C, Gale M Jr, Silverman RH, Colonna M, Akira S, Núñez G: Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux. J Immunol 2014;193:4214-4222.
108.
Biondo C, Mancuso G, Midiri A, Signorino G, Domina M, Lanza Cariccio V, Mohammadi N, Venza M, Venza I, Teti G, Beninati C: The interleukin-1beta/CXCL1/2/neutrophil axis mediates host protection against group B streptococcal infection. Infect Immunity 2014;82:4508-4517.
109.
Verma D, Bivik C, Farahani E, Synnerstad I, Fredrikson M, Enerbäck C, Rosdahl I, Sö-derkvist P: Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma. Pigment Cell Melanoma Res 2012;25:506-513.
110.
Voronov E, Dotan S, Krelin Y, Song X, Elkabets M, Carmi Y, Rider P, Idan Cohen, Romzova M, Kaplanov I, Apte RN: Unique versus redundant functions of IL-1alpha and IL-1beta in the tumor microenvironment. Front Immunol 2013;4:177.
111.
Ungerback J, Belenki D, Jawadul-Hassan A, Fredrikson M, Fransén K, Elander N, Verma D, Söderkvist P: Genetic variation and alterations of genes involved in NFkappaB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer. Carcinogenesis 2012; 33:2126-2134.
112.
Poli G, Brancorsini S, Cochetti G, Barillaro F, Egidi MG, Mearini E: Expression of inflammasome-related genes in bladder cancer and their association with cytokeratin 20 messenger RNA. Urol Oncol 2015;33: 505e1-7.
113.
Miettinen M: Keratin 20: immunohistochemical marker for gastrointestinal, urothelial, and Merkel cell carcinomas. Mod Pathol 1995;8:384-388.
114.
Finger JN, Lich JD, Dare LC, Cook MN, Brown KK, Duraiswami C, Bertin J, Gough PJ: Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J Biol Chem 2012;287:25030-25037.
115.
Boyden ED, Dietrich WF: Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 2006;38:240-244.
116.
Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC: Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell 2007;25:713-724.
117.
Grenier JM, Wang L, Manji GA, Huang WJ, Al-Garawi A, Kelly R, Carlson A, Merriam S, Lora JM, Briskin M, DiStefano PS, Bertin J: Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1. FEBS Lett 2002;530:73-78.
118.
Anand PK, Malireddi RK, Lukens JR, Vogel P, Bertin J, Lamkanfi M, Kanneganti TD: NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 2012;488:389-393.
119.
Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang JP, Brown EM, Frankel G, Levy M, Katz MN, Philbrick WM, Elinav E, Finlay BB, Flavell RA: NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 2014;156: 1045-1059.
120.
Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, Brubaker L, Gai X, Wolfe AJ, Schreckenberger PC: Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol 2014;52:871-876.
121.
Xu W, Yang L, Lee P, Huang WC, Nossa C, Ma Y, Deng FM, Zhou M, Melamed J, Pei Z: Mini-review: perspective of the microbiome in the pathogenesis of urothelial carcinoma. Am J Clin Exp Urol 2014;2:57-61.
122.
Parsons CL: The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology 2007;69: 9-16.
123.
Sanchez-Gomez S, Ferrer-Espada R, Stewart PS, Pitts B, Lohner K, Martinez de Tejada G: Antimicrobial activity of synthetic cationic peptides and lipopeptides derived from human lactoferricin against Pseudomonas aeruginosa planktonic cultures and biofilms. BMC Microbiol 2015;15:137.
124.
Mittal R, Aggarwal S, Sharma S, Chhibber S, Harjai K: Urinary tract infections caused by Pseudomonas aeruginosa: a minireview. J Infect Public Health 2009;2:101-111.
125.
Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, de Almeida L, Rojanasakul Y, Stehlik C: An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 2012;36:464-476.
126.
Vladimer GI, Weng D, Paquette SW, Vanaja SK, Rathinam VA, Aune MH, Conlon JE, Burbage JJ, Proulx MK, Liu Q, Reed G, Mecsas JC, Iwakura Y, Bertin J, Goguen JD, Fitzgerald KA, Lien E: The NLRP12 inflammasome recognizes Yersinia pestis. Immunity 2012;37:96-107.
127.
Sato H, Frank DW: Multi-functional characteristics of the Pseudomonas aeruginosa type III needle-tip protein, PcrV; comparison to orthologs in other Gram-negative bacteria. Front Microbiol 2011;2:142.
128.
Jeru I, Duquesnoy P, Fernandes-Alnemri T, Cochet E, Yu JW, Lackmy-Port-Lis M, Grimprel E, Landman-Parker J, Hentgen V, Marlin S, McElreavey K, Sarkisian T, Grateau G, Alnemri ES, Amselem S: Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A 2008; 105:1614-1619.
129.
Rigante D, Frediani B, Cantarini L: A Comprehensive overview of the hereditary periodic fever syndromes. Clin Rev Allergy Immunol 2016:1-8.
130.
Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM: Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004;430:213-218.
131.
Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Mariathasan S, Dixit VM, Flavell RA, Dietrich WF, Roy CR: The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 2006;7: 318-325.
132.
Miao EA, Ernst RK, Dors M, Mao DP, Aderem A: Pseudomonas aeruginosa activates caspase 1 through Ipaf. Proc Natl Acad Sci USA 2008;105:2562-2567.
133.
Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, Warren SE, Leaf IA, Aderem A: Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci USA 2010;107:3076-3080.
134.
Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA: Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J Exp Med 2007;204:3235-3245.
135.
Miyazaki J, Ba-Thein W, Kumao T, Akaza H, Hayashi H: Identification of a type III secretion system in uropathogenic Escherichia coli. FEMS Microbiol Lett 2002;212: 221-228.
136.
Miano R, Germani S, Vespasiani G: Stones and urinary tract infections. Urol Int 2007; 79(Suppl 1):32-36.
137.
Lopalco G, Rigante D, Giannini M, Galeazzi M, Lapadula G, Iannone F, Cantarini L: Safety profile of anakinra in the management of rheumatologic, metabolic and autoinflammatory disorders. Clin Exp Rheumatol 2016;34:531-538.
138.
Shibata S: A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zasshi 2000;120: 849-862.
139.
Honda H, Nagai Y, Matsunaga T, Okamoto N, Watanabe Y, Tsuneyama K, Hayashi H, Fujii I, Ikutani M, Hirai Y, Muraguchi A, Takatsu K: Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. J Leukoc Biol 2014;91:967-976.
140.
Salla M, Butler MS, Pelingon R, Kaeslin G, Croker DE, Reid JC, Baek JM, Bernhardt PV, Gillam EM, Cooper MA, Robertson AA: Identification, synthesis, and biological evaluation of the major human metabolite of NLRP3 inflammasome inhibitor MCC950. ACS Med Chem Lett 2016;7: 1034-1038.
141.
Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, Meng R, Quong AA, Latz E, Scott CP, Alnemri ES: Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem 2010; 285:9792-9802.
142.
Shahid H, Singh JA: Investigational drugs for hyperuricemia. Expert Opin Investig Drugs 2015;24:1013-1030.
143.
Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, Carreras MC, Poderoso JJ, Gores GJ: The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int 2015;35:953-966.
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