Advertisement

Archives of Pharmacal Research

, Volume 39, Issue 11, pp 1503–1518 | Cite as

Mitochondria and the NLRP3 inflammasome: physiological and pathological relevance

  • Je-Wook Yu
  • Myung-Shik Lee
Review

Abstract

The NLRP3 inflammasome is assembled and activated in certain types of myeloid cells upon sensing microbe-derived toxins or host-derived danger signals. Activation of the NLRP3 inflammasome by endogenous ligands has been discovered in various disorders, including metabolic syndrome, type 2 diabetes, atherosclerosis, gout, reperfusion injury of the heart, neurodegeneration, such as Alzheimer’s disease, chronic kidney diseases, and macular degeneration of the eyes. Despite the potential significance of the NLRP3 inflammasome in the pathogenesis of several diseases, details on the activation mechanism of the NLRP3 inflammasome by a variety of stimulators have yet to be reported. Emerging evidence suggests that mitochondrial events are associated with NLRP3 activation in disease conditions. Mitochondrial dysfunction acts upstream of NLRP3 activation by providing reactive oxygen species (ROS) to trigger NLRP3 oligomerization or by inducing α-tubulin acetylation to relocate mitochondria to the proximity of NLRP3. In addition, mitochondria work as a platform for inflammasome assembly. Mitochondrial events may also lie downstream of NLRP3 activation. While the molecular mechanisms of mitochondrial dysfunction associated with NLRP3 activation are still unclear, they may involve the perturbation of mitochondria by K+ efflux and subsequent intracellular disequilibrium. Thus, mitochondria and NLRP3 machinery appear to be closely interwoven at multiple levels.

Keywords

Interleukin 1 Innate immunity ROS Metabolic syndrome Neurodegeneration 

Notes

Acknowledgements

This study was supported by Bio & Medical Technology Development Program Fund of the National Research Foundation (NRF-2015M3A9B6073846, NRF-2015M3A9B6073856), and the NRF grant (NRF-2013R1A2A2A01067985). M-SL is the recipient of the Global Research Laboratory Grant of the National Research Foundation of Korea (K21004000003-12A0500-00310) and the Ulsan National Institute of Science and Technology Research Fund (2014M3A9D8034459).

Compliance with ethical standards

Conflicts of interest

The authors declare no competing financial interests.

References

  1. Allam R, Lawlor KE, Yu EC, Mildenhall AL, Moujalled DM, Lewis RS, Ke F, Mason KD, White MJ, Stacey KJ, Strasser A, O’Reilly LA, Alexander W, Kile BT, Vaux DL, Vince JE (2014) Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep 15:982–990PubMedPubMedCentralCrossRefGoogle Scholar
  2. 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 (2009) NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–792PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bauernfeind F, Bartok E, Rieger A, Franchi L, Núñez GVH (2011) Reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol 187:613–617PubMedPubMedCentralCrossRefGoogle Scholar
  4. Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit VM, Monack DM (2010) Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med 207:1745–1755PubMedPubMedCentralCrossRefGoogle Scholar
  5. Budai MM, Varga A, Milesz S, Tőzsér J, Benkő S (2013) Aloe vera downregulates LPS-induced inflammatory cytokine production and expression of NLRP3 inflammasome in human macrophages. Mol Immunol 56:471–479PubMedCrossRefGoogle Scholar
  6. Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I, Bubacco L, de Bernard M (2013) Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS One 8:e55375PubMedPubMedCentralCrossRefGoogle Scholar
  7. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O’Neill LA (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 21:263–269Google Scholar
  8. Compan V, Baroja-Mazo A, López-Castejón G, Gomez AI, Martínez CM, Angosto D, Montero MT, Herranz AS, Bazán E, Reimers D, Mulero V, Pelegrín P (2012) Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 37:487–500PubMedCrossRefGoogle Scholar
  9. Conway KE, McConnell BB, Bowring CE, Donald CD, Warren ST, Vertino PM (2000) TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. Cancer Res 60:6236–6242PubMedGoogle Scholar
  10. 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 (2012) Activation of the NLRP3 inflammasome by group B streptococci. J Immunol 188:1953–1960PubMedPubMedCentralCrossRefGoogle Scholar
  11. Dashdorj A, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS (2013) Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines. BMC Med 11:178PubMedPubMedCentralCrossRefGoogle Scholar
  12. Ding Z, Liu S, Wang X, Dai Y, Khaidakov M, Deng X, Fan Y, Xiang D, Mehta JL (2014) LOX-1, mtDNA damage, and NLRP3 inflammasome activation in macrophages: implications in atherogenesis. Cardiovasc Res 103:619–628PubMedPubMedCentralCrossRefGoogle Scholar
  13. Ding W, Guo H, Xu C, Wang B, Zhang M, Ding F (2016) Mitochondrial reactive oxygen species-mediated NLRP3 inflammasome activation contributes to aldosterone-induced renal tubular cells injury. Oncotarget 7:17479–17491PubMedPubMedCentralGoogle Scholar
  14. Doyle SL, Campbell M, Ozaki E, Salomon RG, Mori A, Kenna PF, Farrar GJ, Kiang AS, Humphries MM, Lavelle EC, O’Neill LA, Hollyfield JG, Humphries P (2012) NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat Med 18:791–798PubMedPubMedCentralCrossRefGoogle Scholar
  15. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E (2010) NLRP3 inflammasomes are required for atherosclerosis and activated by cholesterol crystals. Nature 464:1357–1362PubMedPubMedCentralCrossRefGoogle Scholar
  16. Durieux J, Wolff S, Dillin A (2011) The cell-non-autonomous nature of elecdtron transport chain-mediated longevity. Cell 144:79–91PubMedPubMedCentralCrossRefGoogle Scholar
  17. Fernandes-Alnemri T, Kang S, Anderson C, Sagara J, Fitzgerald KA, Alnemri ES (2013) TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J Immunol 191:3995–3999PubMedPubMedCentralCrossRefGoogle Scholar
  18. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Age Dev 128:92–105CrossRefGoogle Scholar
  19. Franchi L, Muñoz-Planillo R, Núñez G (2012) Sensing and reacting to microbes through the inflammasomes. Nat Immunol 13:325–332PubMedPubMedCentralCrossRefGoogle Scholar
  20. Freeman D, Cedillos R, Choyke S, Lukic Z, McGuire K, Marvin S, Burrage AM, Sudholt S, Rana A, O’Connor C, Wiethoff CM, Campbell EM (2013) Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis. PLoS One 8:e62143PubMedPubMedCentralCrossRefGoogle Scholar
  21. Freigang S, Ampenberger F, Weiss A, Kanneganti TD, Iwakura Y, Hersberger M, Kopf M (2013) Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis. Nat Immunol 14:1045–1053PubMedCrossRefGoogle Scholar
  22. Ghonime MG, Shamaa OR, Das S, Eldomany RA, Fernandes-Alnemri T, Alnemri ES, Gavrilin MA, Wewers MD (2014) Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol 192:3881–3888PubMedPubMedCentralCrossRefGoogle Scholar
  23. Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333:1109–1112PubMedPubMedCentralCrossRefGoogle Scholar
  24. Greten FR, Arkan MC, Bollrath J, Hsu LC, Goode J, Miething C, Göktuna SI, Neuenhahn M, Fierer J, Paxian S, Van Rooijen N, Xu Y, O’Cain T, Jaffee BB, Busch DH, Duyster J, Schmid RM, Eckmann L, Karin M (2007) NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta. Cell 130:918–931PubMedPubMedCentralCrossRefGoogle Scholar
  25. Guarda G, Zenger M, Yazdi AS, Schroder K, Ferrero I, Menu P, Tardivel A, Mattmann C, Tschopp J (2011) Differential expression of NLRP3 among hematopoietic cells. J Immunol 186:2529–2534PubMedCrossRefGoogle Scholar
  26. Guo W, Liu W, Jin B, Geng J, Li J, Ding H, Wu X, Xu Q, Sun Y, Gao J (2014a) Asiatic acid ameliorates dextran sulfate sodium-induced murine experimental colitis via suppressing mitochondria-mediated NLRP3 inflammasome activation. Int Immunopharmacol 24:232–238PubMedCrossRefGoogle Scholar
  27. Guo W, Sun Y, Liu W, Wu X, Guo L, Cai P, Wu X, Wu X, Shen Y, Shu Y, Gu Y, Xu Q (2014b) Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer. Autophagy 10:972–985PubMedPubMedCentralCrossRefGoogle Scholar
  28. Gurlo T, Ryazantsev S, Huang CJ, Yeh MW, Reber HA, Hines OJ, O’Brien TD, Glabe CG, Butler PC (2010) Evidence for proteotoxicity in beta cells in type 2 diabetes: toxic islet amyloid polypeptide oligomers form intracellularly in the secretory pathway. Am J Pathol 176:861–869PubMedPubMedCentralCrossRefGoogle Scholar
  29. Gurung P, Anand PK, Malireddi RK, Vande Walle L, Van Opdenbosch N, Dillon CP, Weinlich R, Green DR, Lamkanfi M, Kanneganti TD (2014) FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J Immunol 192:1835–1846PubMedPubMedCentralCrossRefGoogle Scholar
  30. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA (2013) Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341:1250–1253PubMedPubMedCentralCrossRefGoogle Scholar
  31. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-b. Nat Immunol 8:857–865CrossRefGoogle Scholar
  32. Harris J, Hartman M, Roche C, Zeng SG, O’Shea A, Sharp FA, Lambe EM, Creagh EM, Golenbock DT, Tschopp J, Kornfeld H, Fitzgerald KA, Lavelle EC (2011) Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem 286:9587–9597PubMedPubMedCentralCrossRefGoogle Scholar
  33. He Y, Franchi L, Nunez G (2013) TLR agonists stimulate Nlrp3-dependent IL-1beta production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J Immunol 190:334–339PubMedCrossRefGoogle Scholar
  34. He Y, Zeng MY, Yang D, Motro B, Núñez G (2016) NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530:354–357PubMedPubMedCentralCrossRefGoogle Scholar
  35. Henao-Mejia J, Elinav E, Thaiss CA, Flavell RA (2014) Inflammasomes and metabolic disease. Annu Rev Physiol 76:57–78PubMedCrossRefGoogle Scholar
  36. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678PubMedCrossRefGoogle Scholar
  37. Heneka MT, Kummer MP, Latz E (2014) Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14:463–477PubMedCrossRefGoogle Scholar
  38. Hoefkens E, Nys K, John JM, Van Steen K, Arijs I, Van der Goten J, Van Assche G, Agostinis P, Rutgeerts P, Vermeire S, Cleynen I (2013) Autophagy. Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress 9:2046–2055Google Scholar
  39. Honda H, Nagai Y, Matsunaga T, Okamoto N, Watanabe Y, Tsuneyama K, Hayashi H, Fujii I, Ikutani M, Hirai Y, Muraguchi A, Takatsu K (2014) Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. J Leukocyte Biol 96:1087–1100PubMedCrossRefGoogle Scholar
  40. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9:847–856PubMedPubMedCentralCrossRefGoogle Scholar
  41. Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen ZJ (2011) MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146:448–461PubMedPubMedCentralCrossRefGoogle Scholar
  42. Hua KF, Chou JC, Lam Y, Tasi YL, Chen A, Ka SM, Fang Z, Liu ML, Yang FL, Yang YL, Chiu YC, Wu SH (2013) Polyenylpyrrole derivatives inhibit NLRP3 inflammasome activation and inflammatory mediator expression by reducing reactive oxygen species production and mitogen-activated protein kinase activation. PLoS One 8:e76754PubMedPubMedCentralCrossRefGoogle Scholar
  43. Ichinohe T, Yamazaki T, Koshiba T, Yanagi Y (2013) Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection. 110:17963–17968Google Scholar
  44. Idzko M, Hammad H, van Nimwegen M, Kool M, Willart MA, Muskens F, Hoogsteden HC, Luttmann W, Ferrari D, Di Virgilio F, Virchow JCJ, Lambrecht BN (2007) Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat Med 8:913–919CrossRefGoogle Scholar
  45. Inohara N, Ogura Y, Chen FF, Muto A, Nuñez G (2000) Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem 276:2551–2554PubMedCrossRefGoogle Scholar
  46. Ip WK, Medzhitov R (2015) Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat Commun 6:6931PubMedCrossRefGoogle Scholar
  47. Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, Eisenbarth SC, Nauseef WM, Cassel SL, Sutterwala FS (2013) Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 39:311–323PubMedPubMedCentralCrossRefGoogle Scholar
  48. Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, Meng R, Quong AA, Latz E, Scott CP, Alnemri ES (2010) Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem 285:9792–9802PubMedPubMedCentralCrossRefGoogle Scholar
  49. Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES (2012) Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem 287:36617–36622PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kahn SE, Andrikopoulos S, Verchere CB (1999) Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 48:241–253PubMedCrossRefGoogle Scholar
  51. Kanneganti TD, Ozören 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 (2006) Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236PubMedCrossRefGoogle Scholar
  52. Kapetanovic R, Bokil NJ, Sweet MJ (2012) Innate immune perturbations, accumulating DAMPs and inflammasome dysregulation: A ticking time bomb in ageing. Ageing Res Rev 24:40–53CrossRefGoogle Scholar
  53. Katsnelson MA, Rucker LG, Russo HM, Dubyak GR (2015) K + efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling. J Immunol 194:3937–3952PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S, Ikeda U (2011) Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123:594–604PubMedCrossRefGoogle Scholar
  55. 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 (2011) Non-canonical inflammasome activation targets caspase-11. Nature 479:117–121PubMedCrossRefGoogle Scholar
  56. Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszyński A, Forsberg LS, Carlson RW, Dixit VM (2013) Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341:1246–1249PubMedCrossRefGoogle Scholar
  57. 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 (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671PubMedCrossRefGoogle Scholar
  58. Kebaier C, Chamberland RR, Allen IC, Gao X, Broglie PM, Hall JD, Jania C, Doerschuk CM, Tilley SL, Duncan JA (2012) Staphylococcus aureus α-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome. J Infect Dis 205:807–817PubMedPubMedCentralCrossRefGoogle Scholar
  59. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim Y-N, Kim SS, Kim DH, Hur KY, Kim HK, Ko T, Han J, Kim HL, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee M-S (2013) Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 19:83–92PubMedCrossRefGoogle Scholar
  60. Kim HY, Lee HJ, Chang YJ, Pichavant M, Shore SA, Fitzgerald KA, Iwakura Y, Israel E, Bolger K, Faul J, DeKruyff RH, Umetsu DT (2014a) Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med 20:54–61PubMedCrossRefGoogle Scholar
  61. Kim SR, Kim DI, Kim SH, Lee H, Lee KS, Cho SH, Lee YC (2014b) NLRP3 inflammasome activation by mitochondrial ROS in bronchial epithelial cells is required for allergic inflammation. Cell Death Dis 5:e1498PubMedPubMedCentralCrossRefGoogle Scholar
  62. Kim MJ, Bae SH, Ryu JC, Kwon Y, Oh JH, Kwon J, Moon J, Kim K, Miyawaki A, Lee MG, Shin J, Kim YS, Kim CH, Ryter SW, Choi AM, Rhee SG, Ryu JH, Yoon JH (2016) SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages. Autophagy in pressGoogle Scholar
  63. Koprich JB, Reske-Nielsen C, Mithal P, Isacson O (2008) Neuroinflammation mediated by IL-1beta increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson’s disease. J Neuroinflammation 5:8PubMedPubMedCentralCrossRefGoogle Scholar
  64. Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, Deshayes K, Lee WP, Hoffman HM, Dixit VM (2009) Glyburide inhibits the cryopirin/nalp3 inflammasome. J Cell Biol 187:61–70PubMedPubMedCentralCrossRefGoogle Scholar
  65. Lawlor KE, Vince JE (2013) Ambiguities in NLRP3 inflammasome regulation: is there a role for mitochondria? Biochim Biophys Acta 1840:1433–1440PubMedCrossRefGoogle Scholar
  66. Lee GS, Subramanian N, Kim A, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL, Chae JJ (2012) The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2 + and cAMP. Nature 492:123–127PubMedPubMedCentralCrossRefGoogle Scholar
  67. Lee H-M, Kim J-J, Kim HJ, Shong M, Ku BJ, Jo E-K (2013) Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 62:194–204PubMedCrossRefGoogle Scholar
  68. Lee H-Y, Kim J, Quan Y, Lee J-C, Kim M-S, Km S, Bae J-W, Hur KY, Lee MS (2016) Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis. Autophagy in pressGoogle Scholar
  69. Liesa M, Palacín M, Zorzano A (2009) Mitochondrial dynamics in mammalian health and disease. Physiol Rev 89:799–845PubMedCrossRefGoogle Scholar
  70. Lim Y-M, Lim H-J, Hur KY, Quan W, Lee H-Y, Cheon H, Ryu D, Koo SH, Kim HL, Kim J, Komatsu M, Lee M-S (2014) Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat Commun 5:4934PubMedCrossRefGoogle Scholar
  71. Linnane AW, Marzuki S, Ozawa T, Tanaka M (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 8639:642–645CrossRefGoogle Scholar
  72. Liu Z, Zaki MH, Vogel P, Gurung P, Finlay BB, Deng W, Lamkanfi M, Kanneganti TD (2012) Role of inflammasomes in host defense against Citrobacter rodentium infection. J Biol Chem 287:16955–16964PubMedPubMedCentralCrossRefGoogle Scholar
  73. Liu W, Guo W, Wu J, Luo Q, Tao F, Gu Y, Shen Y, Li J, Tan R, Xu Q, Sun Y (2013) A novel benzo[d]imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome. Biochem Pharmacol 85:1504–1512PubMedCrossRefGoogle Scholar
  74. Luo B, Li B, Wang W, Liu X, Xia Y, Zhang C, Zhang M, Zhang Y, An F (2014) NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PLoS One 9:e104771PubMedPubMedCentralCrossRefGoogle Scholar
  75. Lupfer CR, Anand PK, Liu Z, Stokes KL, Vogel P, Lamkanfi M, Kanneganti TD (2014) Reactive oxygen species regulate caspase-11 expression and activation of the non-canonical NLRP3 inflammasome during enteric pathogen infection. PLoS Pathog 10:e1004410PubMedPubMedCentralCrossRefGoogle Scholar
  76. Maejima I, Takahashi A, Omori H, Kimura T, Takabatake Y, Saitoh T, Yamamoto A, Hamasaki M, Noda T, Isaka Y, Yoshimori T (2013) Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J 32:2336–2347PubMedPubMedCentralCrossRefGoogle Scholar
  77. Mao K, Chen S, Chen M, Ma Y, Wang Y, Huang B, He Z, Zeng Y, Hu Y, Sun S, Li J, Wu X, Wang X, Strober W, Chen C, Meng G, Sun B (2013) Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock. Cell Res 23:201–212PubMedPubMedCentralCrossRefGoogle Scholar
  78. Marchetti C, Chojnacki J, Toldo S, Mezzaroma E, Tranchida N, Rose SW, Federici M, Van Tassell BW, Zhang S, Abbate A (2014) A novel pharmacologic inhibitor of the NLRP3 inflammasome limits myocardial injury after ischemia-reperfusion in the mouse. J Cardiovas Pharmacol 63:316–322CrossRefGoogle Scholar
  79. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440Google Scholar
  80. Martin BN, Wang C, Zhang CJ, Kang Z, Gulen MF, Zepp JA, Zhao J, Bian G, Do JS, Min B, Pavicic PG, El-Sanadi C, Fox PL, Akitsu A, Iwakura Y, Sarkar A, Wewers MD, Kaiser WJ, Mocarski ES, Rothenberg ME, Hise AG, Dubyak GR, Ransohoff RM, Li X (2016) T cell-intrinsic ASC critically promotes TH17-mediated experimental autoimmune encephalomyelitis. Nat Immunol 17:583–592PubMedCrossRefGoogle Scholar
  81. Martinon F, Petrilli V, Mayor A, Tardivel A, Tshopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241PubMedCrossRefGoogle Scholar
  82. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, Mullooly GM, Mielke LA, Harris J, Coll RC, Mills KHG, Mok KH, Newsholme P, Nunez G, Yodoi J, Kahn SE, Lavelle EC, O’Neill LAJ (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1b in type 2 diabetes. Nat Immunol 11:897–904PubMedPubMedCentralCrossRefGoogle Scholar
  83. Michelsen KS, Wong WH, Shah PK, Zhang W, Yano J, Doherty TM, Akira S, Rajavashisth TB, Arditi M (2004) Lack of Toll-like receptor 4 or myeloid differntiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci USA 101:10679–10684PubMedPubMedCentralCrossRefGoogle Scholar
  84. Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, Akira S (2013) Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol 14:454–460PubMedCrossRefGoogle Scholar
  85. Misawa T, Saitoh T, Kozaki T, Park S, Takahama M, Akira S (2015) Resveratrol inhibits the acetylated α-tubulin-mediated assembly of the NLRP3-inflammasome. Int Immunol 27:425–434PubMedCrossRefGoogle Scholar
  86. Moon JS, Lee S, Park MA, Siempos II, Haslip M, Lee PJ, Yun M, Kim CK, Howrylak J, Ryter SW, Nakahira K, Choi AMK (2015) UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J Diabetes Invest 125:665–680Google Scholar
  87. Muñoz-Planillo R, Kuffa P, Martínez-Colón G, Smith BL, Rajendiran TM, Núñez G (2013) K + efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38:1142–1153PubMedPubMedCentralCrossRefGoogle Scholar
  88. Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, Horng T (2012) Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci USA 109:11282–11287PubMedPubMedCentralCrossRefGoogle Scholar
  89. Nakahira K, Haspel JA, Rathinam VAK, Lee S-J, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AMK (2011) Autophagy proteins regulates innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 8:222–231CrossRefGoogle Scholar
  90. Parajuli B, Sonobe Y, Horiuchi H, Takeuchi H, Mizuno T, Suzumura A (2013) Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer’s disease. Cell Death Dis 4:e975PubMedPubMedCentralCrossRefGoogle Scholar
  91. Park S, Juliana C, Hong S, Datta P, Hwang I, Fernandes-Alnemri T, Yu JW, Alnemri ES (2013) The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J Immunol 191:4358–4366PubMedCrossRefGoogle Scholar
  92. Park S, Won JH, Hwang I, Hong S, Lee HK, Yu JW (2015) Defective mitochondrial fission augments NLRP3 inflammasome activation. Sci Rep 5:15489PubMedPubMedCentralCrossRefGoogle Scholar
  93. Pelegrin P, Barroso-Gutierrez C, Surprenant A (2008) P2X7 receptor differentially couples to distinct release pathways for IL-1beta in mouse macrophage. J Immunol 180:7147–7157PubMedCrossRefGoogle Scholar
  94. Rathinam VA, Vanaja SK, Fitzgerald KA (2012) Regulation of inflammasome signaling. Nat Immunol 13:333–342PubMedPubMedCentralCrossRefGoogle Scholar
  95. Rawat R, Cohen TV, Ampong B, Francia D, Henriques-Pons A, Hoffman EP, Nagaraju K (2010) Inflammasome up-regulation and activation in dysferlin-deficient skeletal muscle. Am J Pathol 176:2891–2900PubMedPubMedCentralCrossRefGoogle Scholar
  96. Razani B, Feng C, Coleman T, Emanuel R, Wen H, Hwang S, Ting JP, Virgin HW, Kastan MB, Semenkovich CF (2012) Autophagy links inflammasomes to atherosclerotic progression. Cell Metab 15:533–544CrossRefGoogle Scholar
  97. Salminen A, Ojala J, Kaarniranta K, Kauppinen A (2012) Mitochondrial dysfunction and oxidative stress activates inflammasomes: impact on the aging process and age-related diseases. Cell Mol Life Sci 69:2999–3013PubMedCrossRefGoogle Scholar
  98. Salminen A, Kauppinen A, Hiltunen M, Kaarniranta K (2014) Epigenetic regulation of ASC/TMS1 expression: potential role in apoptosis and inflammasome function. Cell Mol Life Sci 71:1855–1864PubMedCrossRefGoogle Scholar
  99. Sandanger Ø, Ranheim T, Vinge LE, Bliksøen M, Alfsnes K, Finsen AV, Dahl CP, Askevold ET, Florholmen G, Christensen G, Fitzgerald KA, Lien E, Valen G, Espevik T, Aukrust P, Yndestad A (2013) The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res 99:164–174PubMedCrossRefGoogle Scholar
  100. Sandanger Ø, Gao E, Ranheim T, Bliksøen M, Kaasbøll OJ, Alfsnes K, Nymo SH, Rashidi A, Ohm IK, Attramadal H, Aukrust P, Vinge LE, Yndestad A (2016) NLRP3 inflammasome activation during myocardial ischemia reperfusion is cardioprotective. Biochem Biophys Res Com 469:1012–1020PubMedCrossRefGoogle Scholar
  101. Schoultz I, Verma D, Halfvarsson J, Törkvist L, Fredrikson M, Sjöqvist U, Lördal M, Tysk C, Lerm M, Söderkvist P, Söderholm JD (2009) Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn’s disease in Swedish men. Am J Gastroenterol 104:1180–1188PubMedCrossRefGoogle Scholar
  102. Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832PubMedCrossRefGoogle Scholar
  103. Seo SU, Kamada N, Muñoz-Planillo R, Kim YG, Kim D, Koizumi Y, Hasegawa M, Himpsl SD, Browne HP, Lawley TD, Mobley HL, Inohara N, Núñez G (2015) Distinct commensals induce interleukin-1β via NLRP3 inflammasome in inflammatory monocytes to promote intestinal inflammation in response to injury. Immunity 42:744–755PubMedPubMedCentralCrossRefGoogle Scholar
  104. Sheng ZH, Cai Q (2012) Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Neurosci 13:77–93CrossRefGoogle Scholar
  105. 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 (2016) NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat Immunol 17:250–258PubMedCrossRefGoogle Scholar
  106. Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN (2013) The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153:348–361PubMedPubMedCentralCrossRefGoogle Scholar
  107. Sun N, Yun J, Liu J, Malide D, Liu C, Rovira II, Holmström KM, Fergusson MM, Yoo YH, Combs CA, Finkel T (2015) Measuring in vivo mitophagy. Mol Cell 60:685–696PubMedPubMedCentralCrossRefGoogle Scholar
  108. Tarallo V, Hirano Y, Gelfand BD, Dridi S, Kerur N, Kim Y, Cho WG, Kaneko H, Fowler BJ, Bogdanovich S, Albuquerque RJ, Hauswirth WW, Chiodo VA, Kugel JF, Goodrich JA, Ponicsan SL, Chaudhuri G, Murphy MP, Dunaief JL, Ambati BK, Ogura Y, Yoo JW, Lee DK, Provost P, Hinton DR, Núñez G, Baffi JZ, Kleinman ME, Ambati J (2012) DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149:847–859PubMedPubMedCentralCrossRefGoogle Scholar
  109. Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkilä S, Wenz T, Ruhanen H, Guse K, Hemminki A, Peltola-Mjøsund KE, Tulkki V, Oresic M, Moraes CT, Pietiläinen K, Hovatta I, Suomalainen A (2010) Mitochondrial myopathy induces a starvation-like response. Hum Mol Genet 19:3948–3958PubMedCrossRefGoogle Scholar
  110. Vandanmagsar B, Youm Y-H, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit WD (2011) The NLRP3 inflammasome instigate obesity-induced inflammation and insulin resistance. Nat Med 15:179–188CrossRefGoogle Scholar
  111. Viganò E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A (2015) Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun 6:8761PubMedPubMedCentralCrossRefGoogle Scholar
  112. Wang X, Jiang W, Yan Y, Gong T, Han J, Tian Z, Zhou R (2014) RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway. Nat Immunol 15:1126–1133PubMedCrossRefGoogle Scholar
  113. Wang Y, Hanus JW, Abu-Asab MS, Shen D, Ogilvy A, Ou J, Chu XK, Shi G, Li W, Wang S, Chan CC (2016) NLRP3 upregulation in retinal pigment epithelium in age-related macular degeneration. Iint J Mol Sci 17:e73CrossRefGoogle Scholar
  114. Watanabe H, Gaide O, Pertrilli V, Martinon F, Contassot E, Roques S, Kummer JA, Tshopp J, French LE (2007) Activation of the IL-1b-processing inflammasome is involved in contact hypersensitivity. J Invest Dermatol 127:1256–1263Google Scholar
  115. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12:408–415PubMedPubMedCentralCrossRefGoogle Scholar
  116. Wiersinga WJ (2011) Current insights in sepsis: from pathogenesis to new treatment targets. Curr Opin Crit Care 17:480–486PubMedCrossRefGoogle Scholar
  117. Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K, Wheeler ML, Cho HC, Popescu N, Coggeshall KM, Arditi M, Underhill DM (2016) Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell 166:624–636PubMedCrossRefGoogle Scholar
  118. Xiang P, Chen T, Mou Y, Wu H, Xie P, Lu G, Gong X, Hu Q, Zhang Y, Ji H (2015) NZ suppresses TLR4/NF-κB signalings and NLRP3 inflammasome activation in LPS-induced RAW264.7 macrophages. Inflamm Res 64:799–808PubMedCrossRefGoogle Scholar
  119. Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C, Guarda G, Tian Z, Tschopp J, Zhou R (2013) Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38:1154–1163PubMedCrossRefGoogle Scholar
  120. Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, Zhou R (2015) Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160:62–73PubMedCrossRefGoogle Scholar
  121. Yang S, Xia C, Li S, Du L, Zhang L, Zhou R (2014) Defective mitophagy driven by dysregulation of rheb and KIF5B contributes to mitochondrial reactive oxygen species (ROS)-induced nod-like receptor 3 (NLRP3) dependent proinflammatory response and aggravates lipotoxicity. Redox Biol 3:63–71PubMedPubMedCentralCrossRefGoogle Scholar
  122. Yaron JR, Gangaraju S, Rao MY, Kong X, Zhang L, Su F, Tian Y, Glenn HL, Meldrum DR (2015) K(+) regulates Ca(2 +) to drive inflammasome signaling: dynamic visualization of ion flux in live cells. Cell Death Dis 6:e1964CrossRefGoogle Scholar
  123. Yasukawa K, Oshiumi H, Takeda M, Ishihara N, Yanagi Y, Seya T, Kawabata S, Koshiba T (2009) Mitofusin 2 inhibits mitochondrial antiviral signaling. Sci Signal 2:ra47Google Scholar
  124. Yazdi AS, Drexler SK, Tschopp J (2010) The role of the inflammasome in nonmyeloid cells. J Clin Immunol 30:623–627PubMedCrossRefGoogle Scholar
  125. Youm YH, Kanneganti TD, Vandanmagsar B, Zhu X, Ravussin A, Adijiang A, Owen JS, Thomas MJ, Francis J, Parks JS, Dixit VD (2012) The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence. Cell Reports 1:56–68PubMedCrossRefGoogle Scholar
  126. Yu J, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, Horng T (2014) Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci USA 111:15514–15519PubMedPubMedCentralCrossRefGoogle Scholar
  127. Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD (2010) The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32:379–391PubMedPubMedCentralCrossRefGoogle Scholar
  128. Zanoni I, Tan Y, Di Gioia M, Broggi A, Ruan J, Shi J, Donado CA, Shao F, Wu H, Springstead JR, Kagan JC (2016) An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352:1232–12236PubMedCrossRefGoogle Scholar
  129. Zhang P, Shao XY, Qi GJ, Chen Q, Bu LL, Chen LJ, Shi J, Ming J, Tian B (2016) Cdk5-dependent activation of neuronal inflammasomes in parkinson’s disease. Mov Disord 31:366–376PubMedCrossRefGoogle Scholar
  130. Zhong Z, Zhai Y, Liang S, Mori Y, Han R, Sutterwala FS, Qiao L (2013) TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun 4:1611PubMedPubMedCentralCrossRefGoogle Scholar
  131. Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Ali SR, McGeough MD, Ellisman MH, Seki E, Gustafsson AB, Hoffman HM, Diaz-Meco MT, Moscat J, Karin M (2016) NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell 164:896–910PubMedCrossRefGoogle Scholar
  132. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J (2010) Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11:136–141PubMedCrossRefGoogle Scholar
  133. Zhou R, Yazdi AS, Menu P, Tshopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–226PubMedCrossRefGoogle Scholar
  134. Zhuang Y, Ding G, Zhao M, Bai M, Yang L, Ni J, Wang R, Jia Z, Huang S, Zhang A (2014) NLRP3 inflammasome mediates albumin-induced renal tubular injury through impaired mitochondrial function. J Biol Chem 289:25101–25111PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2016

Authors and Affiliations

  1. 1.Department of Microbiology and Immunology, BK 21 PLUS Project for Medical ScienceYonsei University College of MedicineSeoulKorea
  2. 2.Severance Biomedical Science Institute and Department of Internal MedicineYonsei University College of MedicineSeoulKorea

Personalised recommendations