Cytokine & Growth Factor Reviews
Volume 22, Issue 5 , Pages 257-276 , October 2011

NOD-like receptors and the innate immune system: Coping with danger, damage and death

  • Kristof Kersse

      Affiliations

    • VIB, Department for Molecular Biomedical Research, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent, Belgium
    • Ghent University, Department of Biomedical Molecular Biology, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent, Belgium
    • ,
  • Mathieu J.M. Bertrand

      Affiliations

    • VIB, Department for Molecular Biomedical Research, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent, Belgium
    • Ghent University, Department of Biomedical Molecular Biology, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent, Belgium
    • ,
  • Mohamed Lamkanfi

      Affiliations

    • Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium
    • Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium
    • These authors share senior authorship.
    • ,
  • Peter Vandenabeele

      Affiliations

    • VIB, Department for Molecular Biomedical Research, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent, Belgium
    • Ghent University, Department of Biomedical Molecular Biology, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent, Belgium
    • These authors share senior authorship.
    • Corresponding Author InformationCorresponding author at: Ghent University, Department of Biomedical Molecular Biology, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium. Tel.: +32 9 3313760; fax: +32 9 3313609.

References 

  1. Kumar H, Kawai T, Akira S. Pathogen recognition in the innate immune response. Biochem J. 2009;420:1–16
  2. Huysamen C, Brown GD. The fungal pattern recognition receptor, dectin-1, and the associated cluster of C-type lectin-like receptors. FEMS Microbiol Lett. 2009;290:121–128
  3. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–832
  4. Wilkins C, Gale M. Recognition of viruses by cytoplasmic sensors. Curr Opin Immunol. 2010;22:41–47
  5. Schroder K, Muruve DA, Tschopp J. Innate immunity: cytoplasmic DNA sensing by the AIM2 inflammasome. Curr Biol. 2009;19:R262–R265
  6. Kim EK, Choi E-J. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta-Mol Basis Dis. 2010;1802:396–405
  7. Vallabhapurapu S, Karin M. Function of NF-kB transcription factors in the immune system. Annu Rev Immunol. 2009;27:693–733
  8. Battistini A. Interferon regulatory factors in hematopoietic cell differentiation and immune regulation. J Interferon Cytokine Res. 2009;29:765–780
  9. Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7:99–109
  10. Ting JPY, Duncan JA, Lei Y. How the noninflammasome NLRs function in the innate immune system. Science. 2010;327:286–290
  11. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, et al. Nod2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16:90–97
  12. Travassos LH, Carneiro LAM, Ramjeet M, Hussey S, Kim Y-G, Magalhaes JG, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010;11:55–62
  13. Allen IC, Moore CB, Schneider M, Lei Y, Davis BK, Scull MA, et al. NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-kappaB signaling pathways. Immunity. 2011;34:854–865
  14. Xia X, Cui J, Wang HY, Zhu L, Matsueda S, Wang Q, et al. NLRX1 negatively regulates TLR-induced NF-kappaB signaling by targeting TRAF6 and IKK. Immunity. 2011;34:843–853
  15. Neerincx A, Lautz K, Menning M, Kremmer E, Zigrino P, Hosel M, et al. A role for the human NLR family member NLRC5 in antiviral responses. J Biol Chem. 2010;285:26223–26232
  16. Harton JA, Linhoff MW, Zhang J, Ting JP-Y. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J Immunol. 2002;169:4088–4093
  17. Kanneganti T-D, Lamkanfi M, Nunez G. Intracellular Nod-like receptors in host defense and disease. Immunity. 2007;27:549–559
  18. Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, et al. The NLR gene family: a standard nomenclature. Immunity. 2008;28:285–287
  19. Danot O, Marquenet E, Vidal-Ingigliardi D, Richet E. Wheel of life, wheel of death: a mechanistic insight into signaling by STAND proteins. Structure. 2009;17:172–182
  20. Krawczyk M, Reith W. Regulation of MHC class II expression, a unique regulatory system identified by the study of a primary immunodeficiency disease. Tissue Antigens. 2006;67:183–197
  21. Reith W, Mach B. THe bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol. 2001;19:331–373
  22. Magalhaes JG, Sorbara MT, Girardin SE, Philpott DJ. What is new with Nods?. Curr Opin Immunol. 2011;23:29–34
  23. Nickerson K, Sisk TJ, Inohara N, Yee CSK, Kennell J, Cho M-C, et al. Dendritic cell-specific MHC class II transactivator contains a caspase recruitment domain that confers potent transactivation activity. J Biol Chem. 2001;276:19089–19093
  24. Collier SM, Moffett P. NB-LRRs work a bait and switch on pathogens. Trends Plant Sci. 2009;14:521–529
  25. Degterev A, Yuan J. Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol. 2008;9:378–390
  26. Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 2008;9:231–241
  27. Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van Ness K, Greenstreet TA, et al. Molecular cloning of the interleukin-1 beta converting enzyme. Science. 1992;256:97–100
  28. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992;356:768–774
  29. Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, et al. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature. 1997;386:619–623
  30. Dinarello CA. Inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–550
  31. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol. 2010;10:89–102
  32. Matthews JS, O’Neill LAJ. Distinct roles for p42/p44 and p38 mitogen-activated protein kinases in the induction of IL-2 by IL-1. Cytokine. 1999;11:643–655
  33. Shirakawa F, Chedid M, Suttles J, Pollok BA, Mizel SB. Interleukin 1 and cyclic AMP induce kappa immunoglobulin light-chain expression via activation of an NF-kappa B-like DNA-binding protein. Mol Cell Biol. 1989;9:959–964
  34. Zhu P, Xiong W, Rodgers G, Qwarnstrom EE. Regulation of interleukin 1 signalling through integrin binding and actin reorganization: disparate effects on NF-kappaB and stress kinase pathways. Biochem J. 1998;330:975–981
  35. Dinarello CA. Blocking interleukin-1β in acute and chronic autoinflammatory diseases. J Intern Med. 2011;269:16–28
  36. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–668
  37. Puren AJ, Fantuzzi G, Dinarello CA. Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1b are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc Natl Acad Sci USA. 1999;96:2256–2261
  38. Kanneganti TD, Lamkanfi M, Kim YG, Chen G, Park JH, Franchi L, et al. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity. 2007;26:433–443
  39. Hiscott J, Marois J, Garoufalis J, D’Addario M, Roulston A, Kwan I, et al. Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol Cell Biol. 1993;13:6231–6240
  40. Franchi L, Eigenbrod T, Nunez G. Cutting edge TNF-a mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol. 2009;183:792–796
  41. Smith DE. The biological paths of IL-1 family members IL-18 and IL-33. J Leukoc Biol. 2011;89:383–392
  42. Dao T, Mehal WZ, Crispe IN. IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. J Immunol. 1998;161:2217–2222
  43. Okamura H, Tsutsui H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, et al. Cloning of a new cytokine that induces IFN-[gamma] production by T cells. Nature. 1995;378:88–91
  44. Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S-I, Okamura H, et al. IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-{gamma} production. J Immunol. 1998;161:3400–3407
  45. Guo L, Wei G, Zhu J, Liao W, Leonard WJ, Zhao K, et al. IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci USA. 2009;106:13463–13468
  46. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev. 2001;12:53–72
  47. Lalor SJ, Dungan LS, Sutton CE, Basdeo SA, Fletcher JM, Mills KH. Caspase-1-processed cytokines IL-1beta and IL-18 promote IL-17 production by gammadelta and CD4T cells that mediate autoimmunity. J Immunol. 2011;186:5738–5748
  48. Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med. 2006;203:1685–1691
  49. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH, et al. IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31:331–341
  50. Lasigliè D, Traggiai E, Federici S, Alessio M, Buoncompagni A, Accogli A, et al. Role of IL-1 beta in the development of human Th17 cells: lesson from NLPR3 mutated patients. PLoS ONE. 2011;6:e20014
  51. Boraschi D, Dinarello CA. IL-18 in autoimmunity: review. Eur Cytokine Netw. 2006;17:224–252
  52. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–490
  53. Lüthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C, et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity. 2009;31:84–98
  54. Malireddi RKS, Ippagunta S, Lamkanfi M, Kanneganti T-D. Cutting edge: proteolytic inactivation of poly(ADP-ribose) polymerase 1 by the Nlrp3 and Nlrc4 inflammasomes. J Immunol. 2010;185:3127–3130
  55. 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
  56. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A, et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol. 2010;11:1136–1142
  57. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder. Immunity. 2004;20:319–325
  58. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004;430:213–218
  59. 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
  60. Elinav E, Strowig T, Kau Andrew L, Henao-Mejia J, Thaiss Christoph A, Booth Carmen J, et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 2011;145:745–757
  61. Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007;25:713–724
  62. Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES. Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J Biol Chem. 2001;276:28309–28313
  63. Kumar Y, Radha V, Swarup G. Interaction with Sug1 enables Ipaf ubiquitination leading to caspase 8 activation and cell death. Biochem J. 2010;427:91–104
  64. Mayor A, Martinon F, De Smedt T, Petrilli V, Tschopp J. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat Immunol. 2007;8:497–503
  65. Duncan JA, Bergstralh DT, Wang Y, Willingham SB, Ye Z, Zimmermann AG, et al. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci. 2007;104:8041–8046
  66. Ye Z, Lich JD, Moore CB, Duncan JA, Williams KL, Ting JP. ATP binding by monarch-1/NLRP12 is critical for its inhibitory function. Mol Cell Biol. 2008;28:1841–1850
  67. Zurek B, Proell M, Wagner RN, Schwarzenbacher R, Kufer TA. Mutational analysis of human Nod1 and Nod2 NACHT domains reveals different modes of activation. Innate Immun. 2011;
  68. Bao Q, Shi Y. Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ. 2006;14:56–65
  69. Riedl SJ, Li W, Chao Y, Schwarzenbacher R, Shi Y. Structure of the apoptotic protease-activating factor 1 bound to ADP. Nature. 2005;434:926–933
  70. Bao Q, Lu W, Rabinowitz JD, Shi Y. Calcium blocks formation of apoptosome by preventing nucleotide exchange in Apaf-1. Mol Cell. 2007;25:181–192
  71. Yuan S, Yu X, Topf M, Ludtke SJ, Wang X, Akey CW. Structure of an apoptosome-procaspase-9 CARD complex. Structure. 2010;18:571–583
  72. Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell. 2002;9:423–432
  73. Jiang X, Wang X. Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem. 2000;275:31199–31203
  74. Diemand AV, Lupas AN. Modeling AAA+ ring complexes from monomeric structures. J Struct Biol. 2006;156:230–243
  75. Masumoto J, Taniguchi S, Ayukawa K, Sarvotham H, Kishino T, Niikawa N, et al. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem. 1999;274:33835–33838
  76. Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J Biol Chem. 2002;277:21119–21122
  77. Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC. CLAN, a novel human CED-4-like gene. Genomics. 2001;75:77–83
  78. Geddes BJ, Wang L, Huang W-J, Lavellee M, Manji GA, Brown M, et al. Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. Biochem Biophys Res Commun. 2001;284:77–82
  79. 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
  80. Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, et al. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 2007;3:e111
  81. Franchi L, Stoolman J, Kanneganti T-D, Verma A, Ramphal R, Nunez G. Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation. Eur J Immunol. 2007;37:3030–3039
  82. Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit VM, Monack DM. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med. 2010;207:1745–1755
  83. Case CL, Shin S, Roy CR. Asc and Ipaf inflammasomes direct distinct pathways for caspase-1 activation in response to Legionella pneumophila. Infect Immun. 2009;77:1981–1991
  84. Broz P, von Moltke J, Jones JW, Vance RE, Monack DM. Differential requirement for caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing. Cell Host Microbe. 2010;8:471–483
  85. Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, et al. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007;14:1590–1604
  86. Chen GY, Liu M, Wang F, Bertin J, Nunez G. A functional role for nlrp6 in intestinal inflammation and tumorigenesis. J Immunol. 2011;186:7187–7194
  87. Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G, Jahn H, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol. 2009;10:266–272
  88. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509–513
  89. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458:514–518
  90. Kerur N, Veettil Mohanan V, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, et al. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi sarcoma-associated herpesvirus infection. Cell Host Microbe. 2011;9:363–375
  91. Poeck H, Bscheider M, Gross O, Finger K, Roth S, Rebsamen M, et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1b production. Nat Immunol. 2010;11:63–69
  92. Rintahaka J, Wiik D, Kovanen PE, Alenius H, Matikainen S. Cytosolic antiviral RNA recognition pathway activates caspases 1 and 3. J Immunol. 2008;180:1749–1757
  93. Chae JJ, Cho YH, Lee GS, Cheng J, Liu PP, Feigenbaum L, et al. Gain-of-function pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice. Immunity. 2011;34:755–768
  94. Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Franchi L, et al. Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem. 2006;281:36560–36568
  95. Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature. 2006;440:233–236
  96. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–232
  97. Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, et al. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity. 2006;24:317–327
  98. Bauernfeind F, Bartok E, Rieger A, Franchi L, Nunez G, Hornung V. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol. 2011;187:613–617
  99. McNeela EA, Burke Ã, Neill I, Baxter DR, Fernandes C, Ferreira VED, et al. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog. 2010;6:e1001191
  100. Toma C, Higa N, Koizumi Y, Nakasone N, Ogura Y, McCoy AJ, et al. Pathogenic vibrio activate NLRP3 inflammasome via cytotoxins and TLR/nucleotide-binding oligomerization domain-mediated NF-{kappa}B signaling. J Immunol. 2010;184:5287–5297
  101. Gross O, Poeck H, Bscheider M, Dostert C, Hannesschläger N, Endres S, et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 2009;459:433–436
  102. Allen IC, Scull MA, Moore CB, Holl EK, McElvania-TeKippe E, Taxman DJ, et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 2009;30:556–565
  103. Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med. 2009;206:79–87
  104. Thomas PG, Dash P, Aldridge JR, Ellebedy AH, Reynolds C, Funk AJ, et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity. 2009;30:566–575
  105. Allen IC, TeKippe EM, Woodford R-MT, Uronis JM, Holl EK, Rogers AB, et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med. 2010;207:1045–1056
  106. Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KSB, McIntire CR, LeBlanc PM, et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity. 2010;32:367–378
  107. Hirota SA, Ng J, Lueng A, Khajah M, Parhar K, Li Y, et al. NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis. Inflamm Bowel Dis. 2010;17:1359–1372
  108. Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti T-D. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity. 2010;32:379–391
  109. Zaki MH, Lamkanfi M, Kanneganti TD. The Nlrp3 inflammasome: contributions to intestinal homeostasis. Trends Immunol. 2011;32:171–179
  110. Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8:458–466
  111. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573–621
  112. Reuter BK, Pizarro TT. Commentary: the role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe?. Eur J Immunol. 2004;34:2347–2355
  113. Bauer C, Duewell P, Mayer C, Lehr HA, Fitzgerald KA, Dauer M, et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut. 2010;59:1192–1199
  114. Tamura K, Fukuda Y, Sashio H, Takeda N, Bamba H, Kosaka T, et al. IL18 polymorphism is associated with an increased risk of Crohn's disease. J Gastroenterol. 2002;37(Suppl. 14):111–116
  115. Villani AC, Lemire M, Fortin G, Louis E, Silverberg MS, Collette C, et al. Common variants in the NLRP3 region contribute to Crohn's disease susceptibility. Nat Genet. 2009;41:71–76
  116. Zhernakova A, Festen EM, Franke L, Trynka G, van Diemen CC, Monsuur AJ, et al. Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am J Hum Genet. 2008;82:1202–1210
  117. Hu B, Elinav E, Huber S, Booth CJ, Strowig T, Jin C, et al. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc Natl Acad Sci. 2010;107:21635–21640
  118. Takagi H, Kanai T, Okazawa A, Kishi Y, Sato T, Takaishi H, et al. Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice. Scand J Gastroenterol. 2003;38:837–844
  119. Lebeis SL, Powell KR, Merlin D, Sherman MA, Kalman D. Interleukin-1 receptor signaling protects mice from lethal intestinal damage caused by the attaching and effacing pathogen Citrobacter rodentium. Infect Immun. 2009;77:604–614
  120. Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, Lukasek K, et al. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1055–G1065
  121. Araki A, Kanai T, Ishikura T, Makita S, Uraushihara K, Iiyama R, et al. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J Gastroenterol. 2005;40:16–23
  122. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–241
  123. Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti T-D. IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J Immunol. 2010;185:4912–4920
  124. Normand S, Delanoye-Crespin A, Bressenot A, Huot L, Grandjean T, Peyrin-Biroulet L, et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc Natl Acad Sci USA. 2011;108:9601–9606
  125. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–241
  126. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9:857–865
  127. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–1361
  128. Rajamaki K, Lappalainen J, Oorni K, Valimaki E, Matikainen S, Kovanen PT, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE. 2010;5:e11765
  129. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci USA. 2008;105:9035–9040
  130. 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
  131. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–856
  132. Yazdi AS, Guarda G, Riteau N, Drexler SK, Tardivel A, Couillin I, et al. Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1a and IL-1b. Proc Natl Acad Sci. 2010;107:19449–19454
  133. Feldmeyer L, Keller M, Niklaus G, Hohl D, Werner S, Beer H-D. The inflammasome mediates UVB-induced activation and secretion of interleukin-12 by keratinocytes. Curr Biol. 2007;17:1140–1145
  134. Watanabe H, Gaide O, Petrilli V, Martinon F, Contassot E, Roques S, et al. Activation of the IL-1b-processing inflammasome is involved in contact hypersensitivity. J Invest Dermatol. 2007;127:1956–1963
  135. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1b in type 2 diabetes. Nat Immunol. 2010;11:897–904
  136. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11:136–140
  137. Vandanmagsar B, Youm Y-H, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;[advance online publication]
  138. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT-H, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011;12:408–415
  139. Kubota T, Koike R. Cryopyrin-associated periodic syndromes: background and therapeutics. Mod Rheumatol. 2010;20:213–221
  140. Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2010;11:12–20
  141. Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002;46:3340–3348
  142. Feldmann J, Prieur A-M, Quartier P, Berquin P, Certain S, Cortis E, et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002;71:198–203
  143. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet. 2001;29:301–305
  144. Kitley JL, Lachmann HJ, Pinto A, Ginsberg L. Neurologic manifestations of the cryopyrin-associated periodic syndrome. Neurology. 2010;74:1267–1270
  145. Klein AK, Horneff G. Rückbildung der Schwerhörigkeit bei einer Patientin mit Muckle–Wells-Syndrom unter Therapie mit Anakinra.[Improvement of sensoneurinal hearing loss in a patient with Muckle–Wells syndrome treated with anakinra.]. Klin Padiatr. 2010;222:266–268
  146. Samuels J, Ozen S. Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever. Curr Opin Rheumatol. 2006;18:108–117
  147. Goldbach-Mansky R, Kastner DL. The prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141–1149
  148. Shinkai K, McCalmont TH, Leslie KS. Cryopyrin-associated periodic syndromes and autoinflammation. Clin Exp Dermatol. 2008;33:1–9
  149. Gris D, Ye Z, Iocca HA, Wen H, Craven RR, Gris P, et al. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J Immunol. 2010;185:974–981
  150. Jha S, Srivastava SY, Brickey WJ, Iocca H, Toews A, Morrison JP, et al. The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J Neurosci. 2010;30:15811–15820
  151. Meissner F, Molawi K, Zychlinsky A. Mutant superoxide dismutase 1-induced IL-1b accelerates ALS pathogenesis. Proc Natl Acad Sci. 2010;107:13046–13050
  152. Lamkanfi M, Kanneganti T-D. Nlrp3 An immune sensor of cellular stress and infection. Int J Biochem Cell Biol. 2010;42:792–795
  153. Brydges SD, Mueller JL, McGeough MD, Pena CA, Misaghi A, Gandhi C, et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity. 2009;30:875–887
  154. Meng G, Zhang F, Fuss I, Kitani A, Strober W. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity. 2009;30:860–874
  155. Maedler K, Dharmadhikari G, Schumann DM, Storling J. Interleukin-1 beta targeted therapy for type 2 diabetes. Expert Opin Biol Ther. 2009;9:1177–1188
  156. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9:R28
  157. Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356:1517–1526
  158. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1b-dependent adaptive immunity against tumors. Nat Med. 2009;15:1170–1178
  159. Perregaux D, Gabel CA. Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J Biol Chem. 1994;269:15195–15203
  160. 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
  161. Fernandes-Alnemri T, Yu J-W, Juliana C, Solorzano L, Kang S, Wu J, et al. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat Immunol. 2010;11:385–393
  162. Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J. 2006;25:5071–5082
  163. Qu Y, Misaghi S, Newton K, Gilmour LL, Louie S, Cupp JE, et al. Pannexin-1 is required for ATP release during apoptosis but not for inflammasome activation. J Immunol. 2011;186:6553–6561
  164. Pelegrin P, Surprenant A. Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway. J Biol Chem. 2007;282:2386–2394
  165. Virginio C, MacKenzie A, North RA, Surprenant A. Kinetics of cell lysis, dye uptake and permeability changes in cells expressing the rat P2X7 receptor. J Physiol. 1999;519(Pt 2):335–346
  166. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol. 2004;5:1166–1174
  167. Dostert C, Guarda G, Romero JF, Menu P, Gross O, Tardivel A, et al. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS ONE. 2009;4:e6510
  168. Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453:1122–1126
  169. Ritter M, Gross O, Kays S, Ruland J, Nimmerjahn r, Saijo FS, et al. Schistosoma mansoni triggers dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses. Proc Natl Acad Sci. 2010;107:20459–20464
  170. Schorn C, Frey B, Lauber K, Janko C, Strysio M, Keppeler H, et al. Sodium overload and water influx activate the NALP3 inflammasome. J Biol Chem. 2011;286:35–41
  171. Cruz CM, Rinna A, Forman HJ, Ventura ALM, Persechini PM, Ojcius DM. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem. 2007;282:2871–2879
  172. Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208:519–533
  173. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 2005;120:649–661
  174. Takada Y, Mukhopadhyay A, Kundu GC, Mahabeleshwar GH, Singh S, Aggarwal BB. Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase. J Biol Chem. 2003;278:24233–24241
  175. van de Veerdonk FL, Smeekens SP, Joosten LAB, Kullberg BJ, Dinarello CA, van der Meer JWM, et al. Reactive oxygen species-independent activation of the IL-1b inflammasome in cells from patients with chronic granulomatous disease. Proc Natl Acad Sci. 2010;107:3030–3033
  176. Meissner F, Molawi K, Zychlinsky A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol. 2008;9:866–872
  177. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84
  178. Tassi S, Carta S, Vene R, Delfino L, Ciriolo MR, Rubartelli A. Pathogen-induced interleukin-1beta processing and secretion is regulated by a biphasic redox response. J Immunol. 2009;183:1456–1462
  179. Carta S, Tassi S, Pettinati I, Delfino L, Dinarello CA, Rubartelli A. The rate of IL-1b secretion in different myeloid cells varies with the extent of redox response to Toll-like receptor triggering. J Biol Chem. 2011;286:27069–27080
  180. Meissner F, Seger RA, Moshous D, Fischer A, Reichenbach J, Zychlinsky A. Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease. Blood. 2010;116:1570–1573
  181. Moore SF, MacKenzie AB. NADPH oxidase NOX2 mediates rapid cellular oxidation following ATP stimulation of endotoxin-primed macrophages. J Immunol. 2009;183:3302–3308
  182. Nakahira K, Haspel JA, Rathinam VAK, Lee S-J, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2010;[advance online publication]
  183. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2010;[advance online publication]
  184. Goldman SJ, Taylor R, Zhang Y, Jin S. Autophagy and the degradation of mitochondria. Mitochondrion. 2010;10:309–315
  185. Saïd-Sadier N, Padilla E, Langsley G, Ojcius DM. Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase. PLoS ONE. 2010;5:e10008
  186. Tiemi Shio M, Eisenbarth SC, Savaria M, Vinet AF, Bellemare M-JE, Harder KW, et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog. 2009;5:e1000559
  187. Underhill DM, Rossnagle E, Lowell CA, Simmons RM. Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood. 2005;106:2543–2550
  188. Robinson MJ, Osorio F, Rosas M, Freitas RP, Schweighoffer E, Gross O, et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. J Exp Med. 2009;206:2037–2051
  189. Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, et al. Syk-dependent cytokine induction by dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005;22:507–517
  190. Wells CA, Salvage-Jones JA, Li X, Hitchens K, Butcher S, Murray RZ, et al. The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans. J Immunol. 2008;180:7404–7413
  191. Hentze H, Lin XY, Choi MSK, Porter AG. 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. 2003;10:956–968
  192. Morishige T, Yoshioka Y, Tanabe A, Yao X, Tsunoda S-I, Tsutsumi Y, et al. Titanium dioxide induces different levels of IL-1[beta] production dependent on its particle characteristics through caspase-1 activation mediated by reactive oxygen species and cathepsin B. Biochem Biophys Res Commun. 2010;392:160–165
  193. Yamasaki K, Muto J, Taylor KR, Cogen AL, Audish D, Bertin J, et al. NLRP3/cryopyrin is necessary for interleukin-1b (IL-1b) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury. J Biol Chem. 2009;284:12762–12771
  194. Niemi K, Teirilä L, Lappalainen J, Rajamäki K, Baumann MH, Öörni K, et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J Immunol. 2011;186:6119–6128
  195. Newman ZL, Leppla SH, Moayeri M. CA-074Me protection against anthrax lethal toxin. Infect Immun. 2009;77:4327–4336
  196. Ichinohe T, Pang IK, Iwasaki A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat Immunol. 2010;11:404–410
  197. Amer A, Franchi L, Kanneganti T-D, Body-Malapel M, Özören N, Brady G, et al. Regulation of legionella phagosome maturation and infection through flagellin and host Ipaf. J Biol Chem. 2006;281:35217–35223
  198. Miao EA, Ernst RK, Dors M, Mao DP, Aderem A. Pseudomonas aeruginosa activates caspase 1 through Ipaf. Proc Natl Acad Sci. 2008;105:2562–2567
  199. Galle M, Schotte P, Haegman M, Wullaert A, Yang HJ, Jin S, et al. The Pseudomonas aeruginosa type III secretion system plays a dual role in the regulation of caspase-1 mediated IL-1beta maturation. J Cell Mol Med. 2008;12:1767–1776
  200. Franchi L, Amer A, Body-Malapel M, Kanneganti T-D, Ozoren N, Jagirdar R, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1[beta] in salmonella-infected macrophages. Nat Immunol. 2006;7:576–582
  201. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol. 2006;7:569–575
  202. Molofsky AB, Byrne BG, Whitfield NN, Madigan CA, Fuse ET, Tateda K, et al. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J Exp Med. 2006;203:1093–1104
  203. Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE. Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog. 2006;2:e18
  204. Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, Warren SE, et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci. 2010;107:3076–3080
  205. Hoffmann C, Galle M, Dilling S, Käppeli R, Müller AJ, Songhet P, et al. In macrophages, caspase-1 activation by SopE and the type III secretion system-1 of S. Typhimurium can proceed in the absence of flagellin. PLoS ONE. 2010;5:e12477
  206. Lightfield KL, Persson J, Brubaker SW, Witte CE, von Moltke J, Dunipace EA, et al. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat Immunol. 2008;9:1171–1178
  207. Bergsbaken T, Fink SL, den Hartigh AB, Loomis WP, Cookson BT. Coordinated host responses during pyroptosis: caspase-1-dependent lysosome exocytosis and inflammatory cytokine maturation. J Immunol. 2011;187:2748–2754
  208. Lamkanfi M, Kanneganti T-D, Van Damme P, Vanden Berghe T, Vanoverberghe I, Vandekerckhove Jl, et al. Targeted peptidecentric proteomics reveals caspase-7 as a substrate of the caspase-1 inflammasomes. Mol Cell Proteomics. 2008;7:2350–2363
  209. Terra JK, Cote CK, France B, Jenkins AL, Bozue JA, Welkos SL, et al. Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of nalp1b/Nlrp1b. J Immunol. 2010;184:17–20
  210. Ibarra JA, Steele-Mortimer O. Salmonella—the ultimate insider. Salmonella virulence factors that modulate intracellular survival. Cell Microbiol. 2009;11:1579–1586
  211. Case CL, Roy CR. Asc modulates the function of NLRC4 in response to infection of macrophages by Legionella pneumophila. mBio. 2011;2:
  212. Lindestam Arlehamn CS, Petrilli V, Gross O, Tschopp J, Evans TJ. The role of potassium in inflammasome activation by bacteria. J Biol Chem. 2010;285:10508–10518
  213. Fink SL, Bergsbaken T, Cookson BT. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc Natl Acad Sci USA. 2008;105:4312–4317
  214. Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet. 2006;38:240–244
  215. Newman ZL, Printz MP, Liu S, Crown D, Breen L, Miller-Randolph S, et al. Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1. PLoS Pathog. 2010;6:e1000906
  216. Witola WH, Mui E, Hargrave A, Liu S, Hypolite M, Montpetit A, et al. NALP1 influences susceptibility to human congenital toxoplasmosis pro-inflammatory cytokine response and fate of T. gondii-infected monocytic cells. Infect. Immun. 2010;IAI.00898–08100
  217. Ali Syed R, Timmer Anjuli M, Bilgrami S, Park Eek J, Eckmann L, Nizet V, et al. Anthrax toxin induces macrophage death by p38 MAPK inhibition but leads to inflammasome activation via ATP leakage. Immunity. 2011;35:34–44
  218. Hsu L-C, Ali SR, McGillivray S, Tseng P-H, Mariathasan S, Humke EW, et al. A Nod2–NALP1 complex mediates caspase-1-dependent IL-1b secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci. 2008;105:7803–7808
  219. Wickliffe KE, Leppla SH, Moayeri M. Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell Microbiol. 2008;10:332–343
  220. Thomas J, Epshtein Y, Chopra A, Ordog B, Ghassemi M, Christman JW, et al. Anthrax lethal factor activates K+ channels to induce IL-1β secretion in macrophages. J Immunol. 2011;186:5236–5243
  221. Muehlbauer SM, Lima H, Goldman DL, Jacobson LS, Rivera J, Goldberg MF, et al. Proteasome inhibitors prevent caspase-1-mediated disease in rodents challenged with anthrax lethal toxin. Am J Pathol. 2010;177:735–743
  222. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med. 2007;356:1216–1225
  223. Zurawek M, Fichna M, Januszkiewicz-Lewandowska D, Gryczynska M, Fichna P, Nowak J. A coding variant in NLRP1 is associated with autoimmune Addison's disease. Hum Immunol. 2010;71:530–534
  224. Jones JW, Kayagaki N, Broz P, Henry T, Newton K, O’Rourke K, et al. Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis. Proc Natl Acad Sci. 2010;107:9771–9776
  225. Rathinam VAK, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol. 2010;11:395–402
  226. Tsuchiya K, Hara H, Kawamura I, Nomura T, Yamamoto T, Daim S, et al. Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. J Immunol. 2010;185:1186–1195
  227. Wu J, Fernandes-Alnemri T, Alnemri E. Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. J Clin Immunol. 2010;30:693–702
  228. Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science. 2009;323:1057–1060
  229. Panchanathan R, Duan X, Shen H, Rathinam VAK, Erickson LD, Fitzgerald KA, et al. Aim2 deficiency stimulates the expression of IFN-inducible Ifi202, a lupus susceptibility murine gene within the Nba2 autoimmune susceptibility locus. J Immunol. 2010;185:7385–7393
  230. Henry T, Brotcke A, Weiss DS, Thompson LJ, Monack DM. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J Exp Med. 2007;204:987–994
  231. Gregory SM, Davis BK, West JA, Taxman DJ, Matsuzawa S-I, Reed JC, et al. Discovery of a Viral NLR Homolog that Inhibits the Inflammasome. Science. 2011;331:330–334
  232. Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell. 2010;140:784–790
  233. Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, Liu PP, et al. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell. 2003;11:591–604
  234. Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Nunez G. Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Biochem Biophys Res Commun. 2003;302:575–580
  235. Papin S, Cuenin S, Agostini L, Martinon F, Werner S, Beer HD, et al. The SPRY domain of pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1[beta] processing. Cell Death Differ. 2007;14:1457–1466
  236. Kaspar R, Gehrke L. Peripheral blood mononuclear cells stimulated with C5a or lipopolysaccharide to synthesize equivalent levels of IL-1 beta mRNA show unequal IL-1 beta protein accumulation but similar polyribosome profiles. J Immunol. 1994;153:277–286
  237. Dinarello C, Ikejima T, Warner S, Orencole S, Lonnemann G, Cannon J, et al. Interleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol. 1987;139:1902–1910
  238. Harris J, Hartman M, Roche C, Zeng SG, O'Shea A, Sharp FA, et al. Autophagy controls IL-1β secretion by targeting Pro-IL-1β for degradation. J Biol Chem. 2011;286:9587–9597
  239. Bedoya F, Sandler LL, Harton JA. Pyrin-only protein 2 modulates NF-kappaB and disrupts ASC:CLR interactions. J Immunol. 2007;178:3837–3845
  240. Bryan N, Dorfleutner A, Kramer S, Yun C, Rojanasakul Y, Stehlik C. Differential splicing of the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) regulates inflammasomes. J Inflamm. 2010;7:23
  241. Druilhe A, Srinivasula SM, Razmara M, Ahmad M, Alnemri ES. Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ. 2001;8:649–657
  242. Humke EW, Shriver SK, Starovasnik MA, Fairbrother WJ, Dixit VM. ICEBERG: a novel inhibitor of interleukin-1beta generation. Cell. 2000;103:99–111
  243. Kersse K, Vanden Berghe T, Lamkanfi M, Vandenabeele P. A phylogenetic and functional overview of inflammatory caspases and caspase-1-related CARD-only proteins. Biochem Soc Trans. 2007;35:1508–1511
  244. Lamkanfi M, Denecker G, Kalai M, D’hondt K, Meeus A, Declercq W, et al. INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1{beta} generation. J Biol Chem. 2004;279:51729–51738
  245. Lee SH, Stehlik C, Reed JC. COP, a caspase recruitment domain-containing protein and inhibitor of caspase-1 activation processing. J Biol Chem. 2001;276:34495–34500
  246. Stehlik C, Krajewska M, Welsh K, Krajewski S, Godzik A, Reed JC. The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-kappa B and pro-caspase-1 regulation. Biochem J. 2003;373:101–113
  247. Dorfleutner A, Bryan NB, Talbott SJ, Funya KN, Rellick SL, Reed JC, et al. Cellular pyrin domain-only protein 2 is a candidate regulator of inflammasome activation. Infect Immun. 2007;75:1484–1492
  248. Stehlik C, Dorfleutner A. COPs and POPs modulators of inflammasome activity. J Immunol. 2007;179:7993–7998
  249. Johnston JB, Barrett JW, Nazarian SH, Goodwin M, Ricuttio D, Wang G, et al. A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection. Immunity. 2005;23:587–598
  250. Rahman MM, Mohamed MR, Kim M, Smallwood S, McFadden G. Co-regulation of NF-kappaB and inflammasome-mediated inflammatory responses by myxoma virus pyrin domain-containing protein M013. PLoS Pathog. 2009;5:e1000635
  251. Dorfleutner A, Talbott SJ, Bryan NB, Funya KN, Rellick SL, Reed JC, et al. A Shope Fibroma virus PYRIN-only protein modulates the host immune response. Virus Genes. 2007;35:685–694
  252. Guarda G, Braun M, Staehli F, Tardivel A, Mattmann C, Förster I, et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity. 2011;34:213–223
  253. Keller M, Ruegg A, Werner S, Beer HD. Active caspase-1 is a regulator of unconventional protein secretion. Cell. 2008;132:818–831
  254. Nickel W, Rabouille C. Mechanisms of regulated unconventional protein secretion. Nat Rev Mol Cell Biol. 2009;10:148–155
  255. Lamkanfi M, Sarkar A, Vande Walle L, Vitari AC, Amer AO, Wewers MD, et al. Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J Immunol. 2010;185:4385–4392
  256. Colotta F, Re F, Muzio M, Bertini R, Polentarutti N, Sironi M, et al. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science. 1993;261:472–475
  257. Giri J, Wells J, Dower S, McCall C, Guzman R, Slack J, et al. Elevated levels of shed type II IL-1 receptor in sepsis. Potential role for type II receptor in regulation of IL-1 responses. J Immunol. 1994;153:5802–5809
  258. Smith DE, Hanna R, Della F, Moore H, Chen H, Farese AM, et al. The soluble form of IL-1 receptor accessory protein enhances the ability of soluble type II IL-1 receptor to inhibit IL-1 action. Immunity. 2003;18:87–96
  259. Carter DB, Deibel MR, Dunn CJ, Tomich CSC, Laborde AL, Slightom JL, et al. Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature. 1990;344:633–638
  260. Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990;343:336–340
  261. Guarda G, Dostert C, Staehli F, Cabalzar K, Castillo R, Tardivel A, et al. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature. 2009;460:269–273
  262. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease. Nature. 2001;411:603–606
  263. Inohara N, Ogura Y, Chen FF, Muto A, Nunez G. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem. 2001;276:2551–2554
  264. Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR, et al. CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep. 2001;2:736–742
  265. Girardin SE, Boneca IG, Viala JR, Chamaillard M, Labigne MA, Thomas SG, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278:8869–8872
  266. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. Host recognition of bacterial muramyl dipeptide mediated through Nod2. J Biol Chem. 2003;278:5509–5512
  267. Girardin SE, Boneca IG, Carneiro LAM, Antignac A, Jehanno M, Viala J, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003;300:1584–1587
  268. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for Nod1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003;4:702–707
  269. Opitz B, Puschel A, Beermann W, Hocke AC, Forster S, Schmeck B, et al. Listeria monocytogenes activated p38 MAPK and induced IL-8 secretion in a nucleotide-binding oligomerization domain 1-dependent manner in endothelial cells. J Immunol. 2006;176:484–490
  270. Travassos LH, Carneiro LA, Girardin SE, Boneca IG, Lemos R, Bozza MT, et al. Nod1 participates in the innate immune response to Pseudomonas aeruginosa. J Biol Chem. 2005;280:36714–36718
  271. Kim JG, Lee SJ, Kagnoff MF. Nod1 is an essential signal transducer in intestinal epithelial cells infected with bacteria that avoid recognition by toll-like receptors. Infect Immun. 2004;72:1487–1495
  272. Zilbauer M, Dorrell N, Elmi A, Lindley KJ, Schuller S, Jones HE, et al. A major role for intestinal epithelial nucleotide oligomerization domain 1 (Nod1) in eliciting host bactericidal immune responses to Campylobacter jejuni. Cell Microbiol. 2007;9:2404–2416
  273. Carneiro LAM, Travassos LH, Soares F, Tattoli I, Magalhaes JG, Bozza MT, et al. Shigella induces mitochondrial dysfunction and cell death in nonmyleoid cells. Cell Host Microbe. 2009;5:123–136
  274. Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med. 2010;16:228–231
  275. Watanabe T, Asano N, Fichtner-Feigl S, Gorelick PL, Tsuji Y, Matsumoto Y, et al. Nod1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest. 2010;120:1645–1662
  276. Silva GK, Gutierrez FRS, Guedes PMM, Horta CV, Cunha LD, Mineo TWP, et al. Cutting edge: nucleotide-binding oligomerization domain 1-dependent responses account for murine resistance against Trypanosoma cruzi infection. J Immunol. 2010;184:1148–1152
  277. Divangahi M, Mostowy S, Coulombe F, Kozak R, Guillot L, Veyrier F, et al. Nod2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity. J Immunol. 2008;181:7157–7165
  278. Gandotra S, Jang S, Murray PJ, Salgame P, Ehrt S. Nucleotide-binding oligomerization domain protein 2-deficient mice control infection with Mycobacterium tuberculosis. Infect Immun. 2007;75:5127–5134
  279. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731–734
  280. Coulombe F, Divangahi M, Veyrier F, de Leseleuc L, Gleason JL, Yang Y, et al. Increased Nod2-mediated recognition of N-glycolyl muramyl dipeptide. J Exp Med. 2009;206:1709–1716
  281. Shaw MH, Reimer T, Sanchez-Valdepenas C, Warner N, Kim Y-G, Fresno M, et al. T cell-intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii. Nat Immunol. 2009;10:1267–1274
  282. Hugot J-P, Chamaillard M, Zouali H, Lesage S, Cezard J-P, Belaiche J, et al. Association of Nod2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001;411:599–603
  283. Miceli-Richard C, Lesage S, Rybojad M, Prieur A-M, Manouvrier-Hanu S, Hafner R, et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29:19–20
  284. Borzutzky A, Fried A, Chou J, Bonilla FA, Kim S, Dedeoglu F. Nod2-associated diseases: bridging innate immunity and autoinflammation. Clin Immunol. 2010;134:251–261
  285. Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-κB. J Biol Chem. 1999;274:14560–14567
  286. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2 a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J Biol Chem. 2001;276:4812–4818
  287. Wertz IE, Dixit VM. Signaling to NF-kB: regulation by ubiquitination. Cold Spring Harbor Perspect Biol. 2010;2:
  288. Pickart CM, Eddins MJ. Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta-Mol Cell Res. 2004;1695:55–72
  289. Malynn BA, Ma A. Ubiquitin makes its mark on immune regulation. Immunity. 2010;33:843–852
  290. Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009;37:937–953
  291. Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M, et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 2006;25:4877–4887
  292. Dikic I, Wakatsuki S, Walters KJ. Ubiquitin-binding domains—from structures to functions. Nat Rev Mol Cell Biol. 2009;10:659–671
  293. Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R, et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell. 2009;136:1098–1109
  294. Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A, et al. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell. 2004;15:535–548
  295. Lécine P, Esmiol S, Métais J-Y, Nicoletti C, Nourry C, McDonald C, et al. The Nod2–RICK complex signals from the plasma membrane. J Biol Chem. 2007;282:15197–15207
  296. Barnich N, Aguirre JE, Reinecker H-C, Xavier R, Podolsky DK. Membrane recruitment of Nod2 in intestinal epithelial cells is essential for nuclear factor-kB activation in muramyl dipeptide recognition. J Cell Biol. 2005;170:21–26
  297. Kufer TA, Kremmer E, Adam AC, Philpott DJ, Sansonetti PJ. The pattern-recognition molecule Nod1 is localized at the plasma membrane at sites of bacterial interaction. Cell Microbiol. 2008;10:477–486
  298. Kaparakis M, Turnbull L, Carneiro L, Firth S, Coleman HA, Parkington HC, et al. Bacterial membrane vesicles deliver peptidoglycan to Nod1 in epithelial cells. Cell Microbiol. 2010;12:372–385
  299. Lee J, Tattoli I, Wojtal KA, Vavricka SR, Philpott DJ, Girardin SE. pH-dependent internalization of muramyl peptides from early endosomes enables Nod1 and Nod2 signaling. J Biol Chem. 2009;284:23818–23829
  300. Marina-Garcia N, Franchi L, Kim Y-G, Hu Y, Smith DE, Boons G-J, et al. Clathrin- and dynamin-dependent endocytic pathway regulates muramyl dipeptide internalization and Nod2 activation. J Immunol. 2009;182:4321–4327
  301. Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, et al. An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem. 2000;275:27823–27831
  302. Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M, et al. RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol. 2007;178:2380–2386
  303. Chin AI, Dempsey PW, Bruhn K, Miller JF, Xu Y, Cheng G. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature. 2002;416:190–194
  304. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G, Janeway CA, et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature. 2002;416:194–199
  305. Lu C, Wang A, Dorsch M, Tian J, Nagashima K, Coyle AJ, et al. Participation of Rip2 in lipopolysaccharide signaling is independent of its kinase activity. J Biol Chem. 2005;280:16278–16283
  306. Nembrini C, Kisielow J, Shamshiev AT, Tortola L, Coyle AJ, Kopf M, et al. The kinase activity of Rip2 determines its stability and consequently Nod1- and Nod2-mediated immune responses. J Biol Chem. 2009;284:19183–19188
  307. Windheim M, Lang C, Peggie M, Plater LA, Cohen P. Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. Biochem J. 2007;404:179–190
  308. Tigno-Aranjuez JT, Asara JM, Abbott DW. Inhibition of RIP2s tyrosine kinase activity limits Nod2-driven cytokine responses. Genes Dev. 2010;24:2666–2677
  309. Bertrand MJM, Doiron K, Labbé K, Korneluk RG, Barker PA, Saleh M. Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors Nod1 and Nod2. Immunity. 2009;30:789–801
  310. Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Nunez G, et al. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J. 2008;27:373–383
  311. Yang Y, Yin C, Pandey A, Abbott D, Sassetti C, Kelliher MA. Nod2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2. J Biol Chem. 2007;282:36223–36229
  312. Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell. 2009;36:831–844
  313. Tokunaga F, Sakata S-I, Saeki Y, Satomi Y, Kirisako T, Kamei K, et al. Involvement of linear polyubiquitylation of NEMO in NF-[kappa]B activation. Nat Cell Biol. 2009;11:123–132
  314. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001;412:346–351
  315. Hayden MS, Ghosh S. Shared principles in NF-[kappa]B signaling. Cell. 2008;132:344–362
  316. Tao M, Scacheri PC, Marinis JM, Harhaj EW, Matesic LE, Abbott DW. ITCH K63-ubiquitinates the Nod2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr Biol. 2009;19:1255–1263
  317. Hsu Y-MS, Zhang Y, You Y, Wang D, Li H, Duramad O, et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat Immunol. 2007;8:198–205
  318. Watanabe T, Kitani A, Murray PJ, Strober W. Nod2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol. 2004;5:800–808
  319. Voss E, Wehkamp J, Wehkamp K, Stange EF, Schroder JM, Harder J. Nod2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem. 2006;281:2005–2011
  320. Noguchi E, Homma Y, Kang X, Netea MG, Ma X. A Crohn's disease-associated Nod2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nat Immunol. 2009;10:471–479
  321. Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature. 2007;446:557–561
  322. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol. 2009;10:1073–1080
  323. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003;4:491–496
  324. Homer CR, Richmond AL, Rebert NA, Achkar J-P, McDonald C. ATG16L1 and Nod2 interact in an autophagy-dependent, anti-bacterial pathway implicated in Crohn's disease pathogenesis. Gastroenterology. 2010;136:1630–1641
  325. Deretic V, Levine B. Autophagy, immunity and microbial adaptations. Cell Host Microbe. 2009;5:527–549
  326. Schmid D, Pypaert M, Munz C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity. 2007;26:79–92
  327. Lipinski S, Till A, Sina C, Arlt A, Grasberger H, Schreiber S, et al. DUOX2-derived reactive oxygen species are effectors of Nod2-mediated antibacterial responses. J Cell Sci. 2009;122:3522–3530
  328. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417–429
  329. Chamaillard M, Philpott D, Girardin SE, Zouali H, Lesage S, Chareyre F, et al. Gene–environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc Natl Acad Sci USA. 2003;100:3455–3460
  330. Li J, Moran T, Swanson E, Julian C, Harris J, Bonen DK, et al. Regulation of IL-8 and IL-1beta expression in Crohn's disease associated Nod2/CARD15 mutations. Hum Mol Genet. 2004;13:1715–1725
  331. Netea MG, Ferwerda G, de Jong DJ, Jansen T, Jacobs L, Kramer M, et al. Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. J Immunol. 2005;174:6518–6523
  332. van Heel DA, Ghosh S, Butler M, Hunt KA, Lundberg AMC, Ahmad T, et al. Muramyl dipeptide and toll-like receptor sensitivity in Nod2-associated Crohn's disease. Lancet. 2005;365:1794–1796
  333. Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, et al. Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci USA. 2005;102:18129–18134
  334. Perez L-H, Butler M, Creasey T, Dzink-Fox J, Gounarides J, Petit S, et al. Direct bacterial killing in vitro by recombinant Nod2 is compromised by Crohn's disease-associated mutations. PLoS ONE. 2010;5:e10915
  335. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207–211
  336. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39:596–604
  337. Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss IJ, et al. Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J Clin Invest. 2008;118:545–559
  338. Kramer M, Netea MG, de Jong DJ, Kullberg BJ, Adema GJ. Impaired dendritic cell function in Crohn's disease patients with Nod2 3020C mutation. J Leukoc Biol. 2006;79:860–866
  339. Maeda S, Hsu L-C, Liu H, Bankston LA, Iimura M, Kagnoff MF, et al. Nod2 mutation in Crohn's disease potentiates NF-kB activity and IL-1b processing. Science. 2005;307:734–738
  340. Netea MG, Ferwerda G, de Jong DJ, Girardin SE, Kullberg BJ, van der Meer JW. Nod2 3020C mutation and the pathogenesis of Crohn's disease: impaired IL-1beta production points to a loss-of-function phenotype. Neth J Med. 2005;63:305–308
  341. Sato T, Machida T, Takahashi S, Iyama S, Sato Y, Kuribayashi K, et al. Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in jurkat cells. J Immunol. 2004;173:285–296
  342. Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T. The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Sci Signal. 2010;3:re4
  343. Gurcel L, Abrami L, Girardin S, Tschopp J, van der Goot FG. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell. 2006;126:1135–1145
  344. McCoy AJ, Koizumi Y, Higa N, Suzuki T. Differential regulation of caspase-1 activation via NLRP3/NLRC4 inflammasomes mediated by aerolysin and type iii secretion system during Aeromonas veronii infection. J Immunol. 2010;185:7077–7084
  345. Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J Immunol. 2008;180:7558–7564
  346. van Lookeren Campagne M, Dixit VM. Immunology: in command of commensals. Nature. 2011;474:42–43
  347. Muñoz-Planillo R, Franchi L, Miller LS, Nunez G. A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome. J Immunol. 2009;183:3942–3948
  348. Ippagunta SK, Brand DD, Luo J, Boyd KL, Calabrese C, Stienstra R, et al. Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD (ASC) in T cell priming is critical for collagen-induced arthritis. J Biol Chem. 2010;285:12454–12462
  349. Kolly L, Karababa M, Joosten LAB, Narayan S, Salvi R, Petrilli V, et al. Inflammatory role of ASC in antigen-induced arthritis is independent of caspase-1, NALP-3, and IPAF. J Immunol. 2009;183:4003–4012
  350. Ellebedy AH, Lupfer C, Ghoneim HE, DeBeauchamp J, Kanneganti T-D, Webby RJ. Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59. Proc Natl Acad Sci. 2011;108:2927–2932
  351. Shigeoka AA, Mueller JL, Kambo A, Mathison JC, King AJ, Hall WF, et al. An inflammasome-independent role for epithelial-expressed Nlrp3 in renal ischemia-reperfusion injury. J Immunol. 2010;185:6277–6285
  352. Chen M, Wang H, Chen W, Meng G. Regulation of adaptive immunity by the NLRP3 inflammasome. Int Immunopharmacol. 2011;11:549–554
  353. Huzarski T, Lener M, Domagala W, Gronwald J, Byrski T, Kurzawski G, et al. The 3020C allele of Nod2 predisposes to early-onset breast cancer. Breast Cancer Res Treat. 2005;89:91–93
  354. Forrest MS, Skibola CF, Lightfoot TJ, Bracci PM, Willett EV, Smith MT, et al. Polymorphisms in innate immunity genes and risk of non-Hodgkin lymphoma. Br J Haematol. 2006;134:180–183
  355. Lener MR, Oszutowska D, Castaneda J, Kurzawski G, Suchy J, Nej-Wolosiak K, et al. Prevalence of the Nod2 3020C mutation in aggregations of breast and lung cancer. Breast Cancer Res Treat. 2006;95:141–145

PII: S1359-6101(11)00045-1

doi: 10.1016/j.cytogfr.2011.09.003

Cytokine & Growth Factor Reviews
Volume 22, Issue 5 , Pages 257-276 , October 2011

Article Tools

* Image Usage & Resolution