The inflammasomes and autoinflammatory syndromes

Annual Review of Pathology: Mechanisms of Disease

Volumn 10, Issue , 2015, Pages 395-424

  Broderick, Lori ^a,c   De Nardo, Dominic ^d   Franklin, Bernardo S ^d   Hoffman, Hal M ^a,b,c,e   Latz, Eicke ^d,f,g,h  

^a UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^b UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^c RADY CHILDREN'S HOSPITAL   (United States)

^d UNIVERSITY HOSPITAL BONN   (Germany)

^e LUDWIG INSTITUTE FOR CANCER RESEARCH   (United States)

^f UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^g GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^h NORWEGIAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Norway)

Author keywords

AIM2; ASC; CAPS; FMF; inflammasomes; NLRC4; NLRP1; NLRP12; NLRP3; NLRP6

Indexed keywords

AIM2 PROTEIN; CRYOPYRIN; INFLAMMASOME; INTERLEUKIN 1; INTERLEUKIN 1BETA CONVERTING ENZYME; NLRC4 PROTEIN; NLRP1 PROTEIN; NLRP12 PROTEIN; NLRP6 PROTEIN; NLRP7 PROTEIN; PROTEIN; UNCLASSIFIED DRUG; URIC ACID;

ALZHEIMER DISEASE; ARTICLE; ATHEROSCLEROSIS; AUTOINFLAMMATORY DISEASE; CYTOKINE RELEASE; ENZYME ACTIVATION; GENE MUTATION; GOUT; HUMAN; IMMUNE SYSTEM; INFECTION; INFLAMMATION; METABOLIC DISORDER; MICROFLORA; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; ANIMAL; AUTOIMMUNE DISEASE; IMMUNOLOGY; SYNDROME;

ANIMALS; AUTOIMMUNE DISEASES; HUMANS; INFLAMMASOMES; INFLAMMATION; SYNDROME;

EID: 84921909014     PISSN: 15534006     EISSN: 15534014     Source Type: Book Series    
DOI: 10.1146/annurev-pathol-012414-040431     Document Type: Article

References (165)

1. Medzhitov R. 2008. Origin and physiological roles of inflammation. Nature 454:428-35
2. Henao-Mejia J, Elinav E, Thaiss CA, Flavell RA. 2014. Inflammasomes and metabolic disease. Annu. Rev. Physiol. 76:57-78
3. Latz E, Xiao TS, Stutz A. 2013. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13:397-411
4. von Moltke J, Ayres JS, Kofoed EM, Chavarria-Smith J, Vance RE. 2013. Recognition of bacteria by inflammasomes. Annu. Rev. Immunol. 31:73-106
5. Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES. 2002. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J. Biol. Chem. 277:21119-22
6. Keller M, Ruegg A, Werner S, Beer HD. 2008. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132:818-31
7. Fink SL, Cookson BT. 2005. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73:1907-16
8. Martinon F, Burns K, Tschopp J. 2002. The inflammasome: a molecular platform triggering complexes. activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10:417-26
9. Park HH, Logette E, Raunser S, Cuenin S, Walz T, et al. 2007. Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128:533-46
10. Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, et al. 2010. The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat. Struct. Mol. Biol. 17:1324-29
11. Lin SC, Lo YC, Wu H. 2010. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465:885-90
12. 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 146:448-61
13. Siegel RM, Martin DA, Zheng L, Ng SY, Bertin J, et al. 1998. Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J. Cell Biol. 141:1243-53
14. Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, et al. 2007. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 14:1590-604
15. Masumoto J, Taniguchi S, Ayukawa K, Sarvotham H, Kishino T, et al. 1999. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J. Biol. Chem. 274:33835-38
16. Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, et al. 2014. Unified polymerizationmechanism for the assembly of ASC-dependent inflammasomes. Cell 156:1193-206
17. Cai X, Chen J, Xu H, Liu S, Jiang QX, et al. 2014. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156:1207-22
18. Wu H. 2013. Higher-order assemblies in a new paradigm of signal transduction. Cell 153:287-92
19. Baroja-Mazo A, Martin-Sanchez F, Gomez AI, Martinez CM, Amores-Iniesta J, et al. 2014. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 15(8):738-48
20. Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A, et al. 2014. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat. Immunol. 15(8):727-37
21. Brydges S, Kastner DL. 2006. The systemic autoinflammatory diseases: inborn errors of the innate immune system. Curr. Top. Microbiol. Immunol. 305:127-60
22. French FMF Consort. 1997. A candidate gene for familial Mediterranean fever. Nat. Genet. 17:25-31
23. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. 2001. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat. Genet. 29:301-5
24. Hoffman HM, Wanderer AA, Broide DH. 2001. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J. Allergy Clin. Immunol. 108:615-20
25. Int. FMF Consort. 1997. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797-807
26. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, et al. 1999. Germlinemutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97:133-44
27. Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, et al. 2008. The Infevers autoinflammatory mutation online registry: update with new genes and functions. Hum. Mutat. 29:803-8
28. Aksentijevich I, Putnam CD, Remmers EF, Mueller JL, Le J, et al. 2007. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 56:1273-85
29. Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Nunez G. 2003. Regulation of cryopyrin/ Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Biochem. Biophys. Res. Commun. 302:575-80
30. Duncan JA, Bergstralh DT, Wang Y, Willingham SB, Ye Z, et al. 2007. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. PNAS 104:8041-46
31. Centola M, Wood G, Frucht DM, Galon J, Aringer M, et al. 2000. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95:3223-31
32. Diaz A, Hu C, Kastner DL, Schaner P, Reginato AM, et al. 2004. Lipopolysaccharide-induced expression of multiple alternatively spliced MEFV transcripts in human synovial fibroblasts: a prominent splice isoform lacks the C-Terminal domain that is highly mutated in familial Mediterranean fever. Arthritis Rheum. 50:3679-89
33. Matzner Y, Abedat S, Shapiro E, Eisenberg S, Bar-Gil-Shitrit A, et al. 2000. Expression of the familial Mediterranean fever gene and activity of the C5a inhibitor in human primary fibroblast cultures. Blood 96:727-31
34. Papin S, Cazeneuve C, Duquesnoy P, Jeru I, Sahali D, Amselem S. 2003. The tumor necrosis factor α-dependent activation of the human Mediterranean fever (MEFV) promoter is mediated by a synergistic interaction between C/EBPβand NFκB p65. J. Biol. Chem. 278:48839-47
35. Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, et al. 2003. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol. Cell 11:591-604
36. Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, et al. 2003. ASC is an activating adaptor for NF-κB and caspase-8-dependent apoptosis. Biochem. Biophys. Res. Commun. 303:69-73
37. Richards N, Schaner P, Diaz A, Stuckey J, Shelden E, et al. 2001. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J. Biol. Chem. 276:39320-29
38. Waite AL, Schaner P, Hu C, Richards N, Balci-Peynircioglu B, et al. 2009. Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin. Exp. Biol. Med. 234:40-52
39. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. 2004. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20:319-25
40. Martinon F, Tschopp J. 2004. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117:561-74
41. Stehlik C, Lee SH, Dorfleutner A, Stassinopoulos A, Sagara J, Reed JC. 2003. Apoptosis-Associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1 activation. J. Immunol. 171:6154-63
42. Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S, et al. 2002. PYPAF7, a novel PYRINcontaining Apaf1-like protein that regulates activation of NF-κB and caspase-1-dependent cytokine processing. J. Biol. Chem. 277:29874-80
43. Stehlik C, Fiorentino L, Dorfleutner A, Bruey JM, Ariza EM, et al. 2002. The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor κB activation pathways. J. Exp.Med. 196:1605-15
44. Kees S, Langevitz P, Zemer D, Padeh S, Pras M, Livneh A. 1997. Attacks of pericarditis as a manifestation of familial Mediterranean fever (FMF). Q. J. Med. 90:643-47
45. Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, et al. 2005. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine 84:1-11
46. Tutar E, Yalcinkaya F, Ozkaya N, Ekim M, Atalay S. 2003. Incidence of pericardial effusion during attacks of familial Mediterranean fever. Heart 89:1257-58
47. Zimand S, Tauber T, Hegesch T, Aladjem M. 1994. Familial Mediterranean fever presenting with massive cardiac tamponade. Clin. Exp. Rheumatol. 12:67-69
48. Livneh A, Madgar I, Langevitz P, Zemer D. 1994. Recurrent episodes of acute scrotum with ischemic testicular necrosis in a patient with familial Mediterranean fever. J. Urol. 151:431-32
49. Majeed HA, Ghandour K, Shahin HM. 2000. The acute scrotum in Arab children with familial Mediterranean fever. Pediatr. Surg. Int. 16:72-74
50. Heller H, Gafni J, Michaeli D, Shahin N, Sohar E, et al. 1966. The arthritis of familial Mediterranean fever (FMF). Arthritis Rheum. 9:1-17
51. Azizi E, Fisher BK. 1976. Cutaneous manifestations of familial Mediterranean fever. Arch. Dermatol. 112:364-66
52. Barzilai A, Langevitz P, Goldberg I, Kopolovic J, Livneh A, et al. 2000. Erysipelas-like erythema of familial Mediterranean fever: clinicopathologic correlation. J. Am. Acad. Dermatol. 42:791-95
53. Int. Soc. Syst. Auto-Inflamm. Dis. 2013. Infevers: an online database for autoinflammatory mutations. Updated July 31. http://fmf.igh.cnrs.fr/ISSAID/infevers/
54. Milhavet F, Cuisset L, Hoffman H, El-Shanti H, Slim R, et al. 2008. The Infevers autoinflammatory mutation online registry: update with new genes and functions. Hum. Mutat. 29:803-8
55. Toutiou I, Lesage S, McDermott M, Cuisset L, Hoffman H, et al. 2004. Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum. Mutat. 24:194-98
56. Sarrauste de Menthiere C, Terriere S, Pugnere D, Ruiz M, Demaille J, Touitou I. 2003. INFEVERS: the registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res. 31:282-85
57. Akar N, Misiroglu M, Yalcinkaya F, Akar E, Cakar N, et al. 2000. MEFV mutations in Turkish patients suffering from familial Mediterranean fever. Hum. Mutat. 15:118-19
58. Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, et al. 1999. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am. J. Hum. Genet. 64:949-62
59. Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, et al. 1999. MEFV-gene analysis in Armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of theM694V homozygous genotype-genetic and therapeutic implications.Am. J. Hum. Genet. 65:88-97
60. Mansour I, Delague V, Cazeneuve C, Dode C, Chouery E, et al. 2001. Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek Catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations. Eur. J. Hum. Genet. 9:51-55
61. Medlej-Hashim M, Rawashdeh M, Chouery E, Mansour I, Delague V, et al. 2000. Genetic screening of fourteen mutations in Jordanian familial Mediterranean fever patients. Hum. Mutat. 15:384
62. Padeh S, Shinar Y, Pras E, Zemer D, Langevitz P, et al. 2003. Clinical and diagnostic value of genetic testing in 216 Israeli children with familial Mediterranean fever. J. Rheumatol. 30:185-90
63. Akarsu AN, Saatci U, Ozen S, Bakkaloglu A, Besbas N, Sarfarazi M. 1997. Genetic linkage study of familial Mediterranean fever (FMF) to 16p13.3 and evidence for genetic heterogeneity in the Turkish population. J. Med. Genet. 34:573-78
64. Domingo C, Touitou I, Bayou A, Ozen S, Notarnicola C, et al. 2000. Familial Mediterranean fever in the 'Chuetas' of Mallorca: a question of Jewish origin or genetic heterogeneity. Eur. J. Hum. Genet. 8:242-46
65. Booth DR, Gillmore JD, Lachmann HJ, Booth SE, Bybee A, et al. 2000. The genetic basis of autosomal dominant familial Mediterranean fever. Q. J. Med. 93:217-21
66. Tennent GA, Lovat LB, Pepys MB. 1995. Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis. PNAS 92:4299-303
67. Balci-Peynircioglu B, Waite AL, Schaner P, Taskiran ZE, Richards N, et al. 2008. Expression of ASC in renal tissues of familial Mediterranean fever patients with amyloidosis: postulating a role for ASC in AA type amyloid deposition. Exp. Biol. Med. 233:1324-33
68. Gavrilin MA, Mitra S, Seshadri S, Nateri J, Berhe F, et al. 2009. Pyrin critical to macrophage IL-1β response to Francisella challenge. J. Immunol. 182:7982-89
69. Papin S, Cuenin S, Agostini L, Martinon F, Werner S, et al. 2007. The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing. Cell Death Differ. 14:1457-66
70. Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, et al. 2008. The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-κB through itsN-Terminal fragment. Blood 112:1794-803
71. Hesker PR, Nguyen M, Kovarova M, Ting JP, Koller BH. 2012. Genetic loss of murine pyrin, the Familial Mediterranean Fever protein, increases interleukin-1βlevels. PLOS ONE 7:e51105
72. Chae JJ, Cho YH, Lee GS, Cheng J, Liu PP, et al. 2011. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1βactivation and severe autoinflammation in mice. Immunity 34:755-68
73. Misawa T, Takahama M, Kozaki T, Lee H, Zou J, et al. 2013. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 14:454-60
74. Balci-Peynircioglu B, Waite AL, Hu C, Richards N, Staubach-Grosse A, et al. 2008. Pyrin, product of the MEFV locus, interacts with the proapoptotic protein, Siva. J. Cell Physiol. 216:595-602
75. Taskiran EZ, Cetinkaya A, Balci-Peynircioglu B, Akkaya YZ, Yilmaz E. 2012. The effect of colchicine on pyrin and pyrin interacting proteins. J. Cell. Biochem. 113:3536-46
76. Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, et al. 2007. Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J. Histochem. Cytochem. 55:443-52
77. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, et al. 2007. NALP1 in vitiligo-Associated multiple autoimmune disease. N. Engl. J. Med. 356:1216-25
78. Magitta NF, Boe Wolff AS, Johansson S, Skinningsrud B, Lie BA, et al. 2009. A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes. Genes Immun. 10:120-24
79. Pontillo A, Vendramin A, Catamo E, Fabris A, Crovella S. 2011. The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease. Am. J. Gastroenterol. 106:539-44
80. Dieude P, Guedj M, Wipff J, Ruiz B, Riemekasten G, et al. 2011. NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis. Ann. Rheum. Dis. 70:668-74
81. Finger JN, Lich JD, Dare LC, Cook MN, Brown KK, et al. 2012. Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J. Biol. Chem. 287:25030-37
82. Levandowski CB, Mailloux CM, Ferrara TM, Gowan K, Ben S, et al. 2013. NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1βprocessing via the NLRP1 inflammasome. PNAS 110:2952-56
83. Okada K, Hirota E, Mizutani Y, Fujioka T, Shuin T, et al. 2004. Oncogenic role of NALP7 in testicular seminomas. Cancer Sci. 95:949-54
84. Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, et al. 2012. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 36:464-76
85. Hodges MD, Rees HC, Seckl MJ, Newlands ES, Fisher RA. 2003. Genetic refinement and physical mapping of a biparental complete hydatidiform mole locus on chromosome 19q13.4. J. Med. Genet. 40:e95
86. Moglabey YB, Kircheisen R, Seoud M, El Mogharbel N, Van den Veyver I, Slim R. 1999. Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum. Mol. Genet. 8:667-71
87. Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, et al. 2006. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat. Genet. 38:300-2
88. Sensi A, Gualandi F, Pittalis MC, Calabrese O, Falciano F, et al. 2000. Mole maker phenotype: possible narrowing of the candidate region. Eur. J. Hum. Genet. 8:641-44
89. Wang CM, Dixon PH, Decordova S, Hodges MD, Sebire NJ, et al. 2009. Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region. J. Med. Genet. 46:569-75
90. Mahadevan S, Wen S, Wan YW, Peng HH, Otta S, et al. 2014. NLRP7 affects trophoblast lineage differentiation, binds to overexpressed YY1 and alters CpG methylation. Hum. Mol. Genet. 23:706-16
91. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, et al. 2006. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1βvia Ipaf. Nat. Immunol. 7:569-75
92. Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, et al. 2010. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. PNAS 107:3076-80
93. Lightfield KL, Persson J, Trinidad NJ, Brubaker SW, Kofoed EM, et al. 2011. Differential requirements for NAIP5 in activation of the NLRC4 inflammasome. Infect. Immun. 79:1606-14
94. Tenthorey JL, Kofoed EM, Daugherty MD, Malik HS, Vance RE. 2014. Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes. Mol. Cell 54:17-29
95. Zhao Y, Yang J, Shi J, Gong YN, Lu Q, et al. 2011. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477:596-600
96. Sutterwala FS, Flavell RA. 2009. NLRC4/IPAF: a CARD carrying member of the NLR family. Clin. Immunol. 130:2-6
97. Canna S, de Jesus AA, Gouni S, Brooks SR, Marrero B, et al. 2014. An activatingNLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat. Genet. 46:1140-46
98. Romberg N, AlMoussawi K, Nelson-WilliamsC, Stiegler AL, Loring E, et al. 2014. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat. Genet. 46:1135-39
99. Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G, et al. 2009. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat. Immunol. 10:266-72
100. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. 2009. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458:509-13
101. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, et al. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-Activating inflammasome with ASC. Nature 458:514-18
102. Schroder K, Muruve DA, Tschopp J. 2009. Innate immunity: cytoplasmic DNA sensing by the AIM2 inflammasome. Curr. Biol. 19:R262-65
103. Jin T, Perry A, Jiang J, Smith P, Curry JA, et al. 2012. Structures of theHIN domain:DNA complexes reveal ligand binding and activationmechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36:561-71
104. Zhang W, Cai Y, Xu W, Yin Z, Gao X, Xiong S. 2013. AIM2 facilitates the apoptotic DNA-induced systemic lupus erythematosus via arbitrating macrophage functionalmaturation. J. Clin. Immunol. 33:925-37
105. Dombrowski Y, Peric M, Koglin S, Kammerbauer C, Goss C, et al. 2011. Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions. Sci. Transl. Med. 3:82ra38
106. Kopfnagel V, Wittmann M, Werfel T. 2011. Human keratinocytes express AIM2 and respond to dsDNA with IL-1βsecretion. Exp. Dermatol. 20:1027-29
107. Fiorentino L, Stehlik C, Oliveira V, Ariza ME, Godzik A, Reed JC. 2002. A novel PAAD-containing protein that modulates NF-κB induction by cytokines tumor necrosis factor-α and interleukin-1β. J. Biol. Chem. 277:35333-40
108. Williams KL, Taxman DJ, Linhoff MW, Reed W, Ting JP-Y. 2003. Cutting edge:Monarch-1: a pyrin/ nucleotide-binding domain/leucine-rich repeat protein that controls classical and nonclassical MHC class I genes. J. Immunol. 170:5354-58
109. Jeru I, Duquesnoy P, Fernandes-Alnemri T, Cochet E, Yu JW, et al. 2008. Mutations in NALP12 cause hereditary periodic fever syndromes. PNAS 105:1614-19
110. Borghini S, Tassi S, Chiesa S, Caroli F, Carta S, et al. 2011. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 63:830-39
111. Jeru I, Hentgen V, Normand S, Duquesnoy P, Cochet E, et al. 2011. Role of interleukin-1βin NLRP12-Associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy. Arthritis Rheum. 63:2142-48
112. Jeru I, Le Borgne G, Cochet E, Hayrapetyan H, Duquesnoy P, et al. 2011. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum. 63:1459-64
113. Lich JD, Williams KL, Moore CB, Arthur JC, Davis BK, et al. 2007. Monarch-1 suppresses non-canonical NF-κB activation and p52-dependent chemokine expression in monocytes. J. Immunol. 178:1256-60
114. Chen GY, Liu M, Wang F, Bertin J, Nunez G. 2011. A functional role for NLRP6 in intestinal inflammation and tumorigenesis. J. Immunol. 186:7187-94
115. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, et al. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745-57
116. Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang JP, et al. 2014. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156:1045-59
117. Anand PK, Malireddi RK, Lukens JR, Vogel P, Bertin J, et al. 2012. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488:389-93
118. Glorioso N, Herrera VL, Didishvili T, Ortu MF, Zaninello R, et al. 2013. Sex-specific effects of NLRP6/AVR and ADM loci on susceptibility to essential hypertension in a Sardinian population. PLOS ONE 8:e77562
119. Ting JP, Duncan JA, Lei Y. 2010. How the noninflammasome NLRs function in the innate immune system. Science 327:286-90
120. Franceschi C, Bonafe M, Valensin S, Olivieri F, De LucaM, et al. 2000. Inflamm-Aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908:244-54
121. Troen BR. 2003. The biology of aging. Mt. Sinai J. Med. 70:3-22
122. Gregor MF, Hotamisligil GS. 2011. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29:415-45
123. Nuki G, Simkin PA. 2006. A concise history of gout and hyperuricemia and their treatment. Arthritis Res. Ther. 8(Suppl. 1):S1
124. Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. 2014. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann. Rheum. Dis. In press. doi: 10.1136/annrheumdis-2013-204463
125. Shi Y, Evans JE, Rock KL. 2003. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516-21
126. Rees F, Hui M, Doherty M. 2014. Optimizing current treatment of gout. Nat. Rev. Rheumatol. 10:271-83
127. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. 2006. Gout-Associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237-41
128. Schumacher HR Jr, Sundy JS, Terkeltaub R, Knapp HR, Mellis SJ, et al. 2012. Rilonacept (interleukin-1 Trap) in the prevention of acute gout flares during initiation of urate-lowering therapy: results of a phase II randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 64:876-84
129. So A, De Smedt T, Revaz S, Tschopp J. 2007. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 9:R28
130. Kool M, Willart MA, van Nimwegen M, Bergen I, Pouliot P, et al. 2011. An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34:527-40
131. World Health Organ. 2014. World Health Statistics 2014. Geneva: WHO Press. http://www.who. int/gho/publications/world-health-statistics/2014/en/
132. Lusis AJ. 2000. Atherosclerosis. Nature 407:233-41
133. Wright SD, Burton C, Hernandez M, Hassing H, Montenegro J, et al. 2000. Infectious agents are not necessary for murine atherogenesis. J. Exp. Med. 191:1437-42
134. Grebe A, Latz E. 2013. Cholesterol crystals and inflammation. Curr. Rheumatol. Rep. 15:313
135. Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, et al. 2013. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14:812-20
136. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, et al. 2010. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11:155-61
137. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, et al. 2010. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357-61
138. Freigang S, Ampenberger F, Spohn G, Heer S, Shamshiev AT, et al. 2011. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur. J. Immunol. 41:2040-51
139. Rajamaki K, Lappalainen J, Oorni K, Valimaki E, Matikainen S, et al. 2010. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLOS ONE 5:e11765
140. Gage J, Hasu M, Thabet M, Whitman SC. 2012. Caspase-1 deficiency decreases atherosclerosis in apolipoprotein E-null mice. Can. J. Cardiol. 28:222-29
141. Usui F, Shirasuna K, Kimura H, Tatsumi K, Kawashima A, et al. 2012. Critical role of caspase-1 in vascular inflammation and development of atherosclerosis inWestern diet-fed apolipoproteinE-deficient mice. Biochem. Biophys. Res. Commun. 425:162-68
142. Elhage R, Maret A, Pieraggi MT, Thiers JC, Arnal JF, Bayard F. 1998. Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein E-deficient mice. Circulation 97:242-44
143. Olofsson PS, Sheikine Y, Jatta K, Ghaderi M, Samnegard A, et al. 2009. A functional interleukin-1 receptor antagonist polymorphism influences atherosclerosis development. The interleukin-1β:interleukin-1 receptor antagonist balance in atherosclerosis. Circ. J. 73:1531-36
144. De Nardo D, Latz E. 2011. NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol. 32:373-79
145. Freigang S, Ampenberger F, Weiss A, Kanneganti TD, Iwakura Y, et al. 2013. Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis. Nat. Immunol. 14:1045-53
146. Fettelschoss A, Kistowska M, LeibundGut-Landmann S, Beer HD, Johansen P, et al. 2011. Inflammasome activation and IL-1βtarget IL-1αfor secretion as opposed to surface expression. PNAS 108:18055-60
147. Ridker PM, Howard CP, Walter V, Everett B, Libby P, et al. 2012. Effects of interleukin-1βinhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 126:2739-48
148. Ridker PM, Thuren T, Zalewski A, Libby P. 2011. Interleukin-1βinhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am. Heart J. 162:597-605
149. Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, et al. 2012. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J. Neuroinflamm. 9:151
150. Prinz M, Priller J, Sisodia SS, Ransohoff RM. 2011. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14:1227-35
151. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, et al. 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9:857-65
152. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, et al. 2013. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493:674-78
153. Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, et al. 2013. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18:519-32
154. Stienstra R, Joosten LA, Koenen T, van Tits B, van Diepen JA, et al. 2010. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12:593-605
155. Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, et al. 2011. Inflammasome is a central player in the induction of obesity and insulin resistance. PNAS 108:15324-29
156. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, et al. 2011. TheNLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17:179-88
157. Wen H, Gris D, Lei Y, Jha S, Zhang L, et al. 2011. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12:408-15
158. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. 2010. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11:136-40
159. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, et al. 2010. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides amechanism for enhanced IL-1βin type 2 diabetes. Nat. Immunol. 11:897-904
160. Ayres JS. 2013. Inflammasome-microbiota interplay in host physiologies. Cell Host Microbe 14:491-97
161. Cho I, Blaser MJ. 2012. The human microbiome: at the interface of health and disease. Nat. Rev. Genet. 13:260-70
162. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, et al. 2012. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482:179-85
163. Marie J, Kovacs D, Pain C, Jouary T, Cota C, et al. 2014. Inflammasome activation and vitiligo/ nonsegmental vitiligo progression. Br. J. Dermatol. 170:816-23
164. Zurawek M, Fichna M, Januszkiewicz-Lewandowska D, Gryczynska M, Fichna P, Nowak J. 2010. A coding variant in NLRP1 is associated with autoimmune Addison's disease. Hum. Immunol. 71:530-34
165. Alkhateeb A, Jarun Y, Tashtoush R. 2013. Polymorphisms in NLRP1 gene and susceptibility to autoimmune thyroid disease. Autoimmunity 46:215-21