1887
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Inflammasomes in Myeloid Cells: Warriors Within

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Authors: Sushmita Jha1, W. June Brickey2, Jenny Pan-Yun Ting3,4
  • Editor: Siamon Gordon5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Bio-Sciences and Bio-Engineering, Indian Institute of Technology Jodhpur, Rajasthan, 342011, India; 2: Lineberger Comprehensive Cancer Center; 3: Lineberger Comprehensive Cancer Center; 4: Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599; 5: Oxford University, Oxford, United Kingdom
    • Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0049-2016
  • Received 09 September 2016 Accepted 16 December 2016 Published 20 January 2017
  • Sushmita Jha, [email protected]
image of Inflammasomes in Myeloid Cells: Warriors Within
    Preview this microbiology spectrum article:
    Preview Magnify
    Zoom in
    Zoomout

    Inflammasomes in Myeloid Cells: Warriors Within, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/5/1/MCHD-0049-2016-1.gif /docserver/preview/fulltext/microbiolspec/5/1/MCHD-0049-2016-2.gif

  • Abstract:

    The inflammasome is a large multimeric protein complex comprising an effector protein that demonstrates specificity for a variety of activators or ligands; an adaptor molecule; and procaspase-1, which is converted to caspase-1 upon inflammasome activation. Inflammasomes are expressed primarily by myeloid cells and are located within the cell. The macromolecular inflammasome structure can be visualized by cryo-electron microscopy. This complex has been found to play a role in a variety of disease models in mice, and several have been genetically linked to human diseases. In most cases, the effector protein is a member of the NLR (nucleotide-binding domain leucine-rich repeat-containing) or NOD (nucleotide oligomerization domain)-like receptor protein family. However, other effectors have also been described, with the most notable being AIM-2 (absent in melanoma 2), which recognizes DNA to elicit inflammasome function. This review will focus on the role of the inflammasome in myeloid cells and its role in health and disease.

  • Citation: Jha S, Brickey W, Ting J. 2017. Inflammasomes in Myeloid Cells: Warriors Within. Microbiol Spectrum 5(1):MCHD-0049-2016. doi:10.1128/microbiolspec.MCHD-0049-2016.

References

1. Harton JA, Linhoff MW, Zhang J, Ting JP. 2002. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J Immunol 169:4088–4093. [PubMed]
2. Inohara N, Nuñez G. 2003. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3:371–382.[PubMed]
3. Tschopp J, Martinon F, Burns K. 2003. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 4:95–104.[PubMed]
4. Davis BK, Wen H, Ting JP. 2010. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 29:707–735. [PubMed]
5. Ting JP, Davis BK. 2005. CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol 23:387–414. [PubMed]
6. Ausubel FM. 2005. Are innate immune signaling pathways in plants and animals conserved? Nat Immunol 6:973–979. [PubMed]
7. Davis BK, Roberts RA, Huang MT, Willingham SB, Conti BJ, Brickey WJ, Barker BR, Kwan M, Taxman DJ, Accavitti-Loper MA, Duncan JA, Ting JP. 2011. Cutting edge: NLRC5-dependent activation of the inflammasome. J Immunol 186:1333–1337. [PubMed]
8. Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, van Bruggen R, Tschopp J. 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 55:443–452. [PubMed]
9. Allen IC. 2014. Non-inflammasome forming NLRs in inflammation and tumorigenesis. Front Immunol 5:169. doi:10.3389/fimmu.2014.00169. [PubMed]
10. Claes AK, Zhou JY, Philpott DJ. 2015. NOD-like receptors: guardians of intestinal mucosal barriers. Physiology (Bethesda) 30:241–250. [PubMed]
11. Clay GM, Sutterwala FS, Wilson ME. 2014. NLR proteins and parasitic disease. Immunol Res 59:142–152. [PubMed]
12. Hlaing T, Guo RF, Dilley KA, Loussia JM, Morrish TA, Shi MM, Vincenz C, Ward PA. 2001. Molecular cloning and characterization of DEFCAP-L and -S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins. J Biol Chem 276:9230–9238. [PubMed]
13. Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC. 2001. A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. J Biol Chem 276:9239–9245. [PubMed]
14. Yuan JY, Horvitz HR. 1990. The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death. Dev Biol 138:33–41. [PubMed]
15. Martinon F, Burns K, Tschopp J. 2002. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell 10:417–426. [PubMed]
16. Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC. 2007. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell 25:713–724. [PubMed]
17. Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, Flavell RA, Girardin SE, Godzik A, Harton JA, Hoffman HM, Hugot JP, Inohara N, Mackenzie A, Maltais LJ, Nunez G, Ogura Y, Otten LA, Philpott D, Reed JC, Reith W, Schreiber S, Steimle V, Ward PA. 2008. The NLR gene family: a standard nomenclature. Immunity 28:285–287. [PubMed]
18. Sastalla I, Crown D, Masters SL, McKenzie A, Leppla SH, Moayeri M. 2013. Transcriptional analysis of the three Nlrp1 paralogs in mice. BMC Genomics 14:188. doi:10.1186/1471-2164-14-188. [PubMed]
19. Dwivedi M, Laddha NC, Mansuri MS, Marfatia YS, Begum R. 2013. Association of NLRP1 genetic variants and mRNA overexpression with generalized vitiligo and disease activity in a Gujarat population. Br J Dermatol 169:1114–1125. [PubMed]
20. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA. 2007. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 356:1216–1225. [PubMed]
21. Levandowski CB, Mailloux CM, Ferrara TM, Gowan K, Ben S, Jin Y, McFann KK, Holland PJ, Fain PR, Dinarello CA, Spritz RA. 2013. NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome. Proc Natl Acad Sci U S A 110:2952–2956. [PubMed]
22. Magitta NF, Bøe Wolff AS, Johansson S, Skinningsrud B, Lie BA, Myhr KM, Undlien DE, Joner G, Njølstad PR, Kvien TK, Førre Ø, Knappskog PM, Husebye ES. 2009. A coding polymorphism in NALP1 confers risk for autoimmune Addison’s disease and type 1 diabetes. Genes Immun 10:120–124. [PubMed]
23. Newman ZL, Printz MP, Liu S, Crown D, Breen L, Miller-Randolph S, Flodman P, Leppla SH, Moayeri M. 2010. Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1. PLoS Pathog 6:e1000906. doi:10.1371/journal.ppat.1000906.
24. Terra JK, Cote CK, France B, Jenkins AL, Bozue JA, Welkos SL, LeVine SM, Bradley KA. 2010. Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b. J Immunol 184:17–20. [PubMed]
25. Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM, Karin M. 2008. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1β secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci U S A 105:7803–7808. [PubMed]
26. Chavarría-Smith J, Vance RE. 2013. Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor. PLoS Pathog 9:e1003452. doi:10.1371/journal.ppat.1003452.
27. Levinsohn JL, Newman ZL, Hellmich KA, Fattah R, Getz MA, Liu S, Sastalla I, Leppla SH, Moayeri M. 2012. Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLoS Pathog 8:e1002638. doi:10.1371/journal.ppat.1002638. [PubMed]
28. Hellmich KA, Levinsohn JL, Fattah R, Newman ZL, Maier N, Sastalla I, Liu S, Leppla SH, Moayeri M. 2012. Anthrax lethal factor cleaves mouse Nlrp1b in both toxin-sensitive and toxin-resistant macrophages. PLoS One 7:e49741. doi:10.1371/journal.pone.0049741.
29. Kovarova M, Hesker PR, Jania L, Nguyen M, Snouwaert JN, Xiang Z, Lommatzsch SE, Huang MT, Ting JP, Koller BH. 2012. NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice. J Immunol 189:2006–2016. [PubMed]
30. Reubold TF, Hahne G, Wohlgemuth S, Eschenburg S. 2014. Crystal structure of the leucine-rich repeat domain of the NOD-like receptor NLRP1: implications for binding of muramyl dipeptide. FEBS Lett 588:3327–3332. [PubMed]
31. Witola WH, Mui E, Hargrave A, Liu S, Hypolite M, Montpetit A, Cavailles P, Bisanz C, Cesbron-Delauw MF, Fournié GJ, McLeod R. 2011. NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells. Infect Immun 79:756–766. [PubMed]
32. Ewald SE, Chavarria-Smith J, Boothroyd JC. 2014. NLRP1 is an inflammasome sensor for Toxoplasma gondii. Infect Immun 82:460–468. [PubMed]
33. Gorfu G, Cirelli KM, Melo MB, Mayer-Barber K, Crown D, Koller BH, Masters S, Sher A, Leppla SH, Moayeri M, Saeij JP, Grigg ME. 2014. Dual role for inflammasome sensors NLRP1 and NLRP3 in murine resistance to Toxoplasma gondii. mBio 5:e01117-13. doi:10.1128/mBio.01117-13.
34. Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O’Donnell JA, McArthur K, Baldwin TM, Chevrier S, Nowell CJ, Cengia LH, Henley KJ, Collinge JE, Kastner DL, Feigenbaum L, Hilton DJ, Alexander WS, Kile BT, Croker BA. 2012. NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity 37:1009–1023. [PubMed]
35. Chi W, Li F, Chen H, Wang Y, Zhu Y, Yang X, Zhu J, Wu F, Ouyang H, Ge J, Weinreb RN, Zhang K, Zhuo Y. 2014. Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma. Proc Natl Acad Sci U S A 111:11181–11186. [PubMed]
36. de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM, Dietrich WD, Keane RW. 2009. Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 29:1251–1261. [PubMed]
37. Williams TM, Leeth RA, Rothschild DE, Coutermarsh-Ott SL, McDaniel DK, Simmons AE, Heid B, Cecere TE, Allen IC. 2015. The NLRP1 inflammasome attenuates colitis and colitis-associated tumorigenesis. J Immunol 194:3369–3380. [PubMed]
38. Murphy AJ, Kraakman MJ, Kammoun HL, Dragoljevic D, Lee MK, Lawlor KE, Wentworth JM, Vasanthakumar A, Gerlic M, Whitehead LW, DiRago L, Cengia L, Lane RM, Metcalf D, Vince JE, Harrison LC, Kallies A, Kile BT, Croker BA, Febbraio MA, Masters SL. 2016. IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome. Cell Metab 23:155–164. [PubMed]
39. de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW. 2008. A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci 28:3404–3414. [PubMed]
40. de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM, Dietrich WD, Keane RW. 2009. Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 29:1251–1261. [PubMed]
41. Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A, Engels G, Brenker C, Nordhoff M, Mirandola SR, Al-Amoudi A, Mangan MS, Zimmer S, Monks BG, Fricke M, Schmidt RE, Espevik T, Jones B, Jarnicki AG, Hansbro PM, Busto P, Marshak-Rothstein A, Hornemann S, Aguzzi A, Kastenmüller W, Latz E. 2014. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat Immunol 15:727–737. [PubMed]
42. 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 29:301–305. [PubMed]
43. Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF, Austin F, Remmers EF, Balow JE, Jr, Rosenzweig S, Komarow H, Shoham NG, Wood G, Jones J, Mangra N, Carrero H, Adams BS, Moore TL, Schikler K, Hoffman H, Lovell DJ, Lipnick R, Barron K, O’Shea JJ, Kastner DL, Goldbach-Mansky R. 2002. 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 46:3340–3348. [PubMed]
44. Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR, Lachmann HJ, Bybee A, Gaudet R, Woo P, Feighery C, Cotter FE, Thome M, Hitman GA, Tschopp J, McDermott MF. 2002. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum 46:2445–2452. [PubMed]
45. Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, de Saint Basile G. 2002. 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 71:198–203. [PubMed]
46. Manji GA, Wang L, Geddes BJ, Brown M, Merriam S, Al-Garawi A, Mak S, Lora JM, Briskin M, Jurman M, Cao J, DiStefano PS, Bertin J. 2002. PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-κB. J Biol Chem 277:11570–11575. [PubMed]
47. Guarda G, Zenger M, Yazdi AS, Schroder K, Ferrero I, Menu P, Tardivel A, Mattmann C, Tschopp J. 2011. Differential expression of NLRP3 among hematopoietic cells. J Immunol 186:2529–2534. [PubMed]
48. Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Franchi L, Taraporewala ZF, Miller D, Patton JT, Inohara N, Núñez G. 2006. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem 281:36560–36568. [PubMed]
49. Kanneganti TD, Ozören N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Núñez G. 2006. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236. [PubMed]
50. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM. 2006. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232. [PubMed]
51. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. 2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241. [PubMed]
52. Shi Y, Evans JE, Rock KL. 2003. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521. [PubMed]
53. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT. 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 9:857–865. [PubMed]
54. Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR. 2006. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol 177:1272–1281. [PubMed]
55. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, Carter AB, Rothman PB, Flavell RA, Sutterwala FS. 2008. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A 105:9035–9040. [PubMed]
56. Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. 2008. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674–677. [PubMed]
57. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E. 2008. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9:847–856. [PubMed]
58. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nuñez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. 2010. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361. [PubMed]
59. Rajamäki K, Lappalainen J, Oörni K, Välimäki E, Matikainen S, Kovanen PT, Eklund KK. 2010. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One 5:e11765. doi:10.1371/journal.pone.0011765.
60. Li H, Willingham SB, Ting JP, Re F. 2008. Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J Immunol 181:17–21. [PubMed]
61. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, Mullooly N, Mielke LA, Harris J, Coll RC, Mills KH, Mok KH, Newsholme P, Nuñez G, Yodoi J, Kahn SE, Lavelle EC, O’Neill LA. 2010. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol 11:897–904. [PubMed]
62. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. 2011. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17:179–188. [PubMed]
63. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP. 2011. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12:408–415. [PubMed]
64. Shio MT, Eisenbarth SC, Savaria M, Vinet AF, Bellemare MJ, Harder KW, Sutterwala FS, Bohle DS, Descoteaux A, Flavell RA, Olivier M. 2009. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog 5:e1000559. doi:10.1371/journal.ppat.1000559.
65. Abdul-Sater AA, Tattoli I, Jin L, Grajkowski A, Levi A, Koller BH, Allen IC, Beaucage SL, Fitzgerald KA, Ting JP, Cambier JC, Girardin SE, Schindler C. 2013. Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome. EMBO Rep 14:900–906. [PubMed]
66. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E. 2009. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–791. [PubMed]
67. Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galán JE, Askenase PW, Flavell RA. 2006. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24:317–327. [PubMed]
68. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM. 2004. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–218. [PubMed]
69. Shao W, Yeretssian G, Doiron K, Hussain SN, Saleh M. 2007. The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock. J Biol Chem 282:36321–36329. [PubMed]
70. Keller M, Rüegg A, Werner S, Beer HD. 2008. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132:818–831. [PubMed]
71. Li P, Allen H, Banerjee S, Seshadri T. 1997. Characterization of mice deficient in interleukin-1β converting enzyme. J Cell Biochem 64:27–32. [PubMed]
72. Compan V, Baroja-Mazo A, López-Castejón G, Gomez AI, Martínez CM, Angosto D, Montero MT, Herranz AS, Bazán E, Reimers D, Mulero V, Pelegrín P. 2012. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 37:487–500. [PubMed]
73. Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL, Chae JJ. 2012. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2 + and cAMP. Nature 492:123–127. [PubMed]
74. Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, Horng T. 2012. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A 109:11282–11287. [PubMed]
75. Zhong Z, Zhai Y, Liang S, Mori Y, Han R, Sutterwala FS, Qiao L. 2013. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun 4:1611. doi:10.1038/ncomms2608. [PubMed]
76. Schorn C, Frey B, Lauber K, Janko C, Strysio M, Keppeler H, Gaipl US, Voll RE, Springer E, Munoz LE, Schett G, Herrmann M. 2011. Sodium overload and water influx activate the NALP3 inflammasome. J Biol Chem 286:35–41. [PubMed]
77. Cruz CM, Rinna A, Forman HJ, Ventura AL, Persechini PM, Ojcius DM. 2007. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem 282:2871–2879. [PubMed]
78. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, Rentsendorj A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M. 2012. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401–414. [PubMed]
79. Nakahira K, Haspel JA, Rathinam VAK, Lee S-J, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AMK. 2011. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222–230. [PubMed]
80. Boschan C, Witt O, Lohse P, Foeldvari I, Zappel H, Schweigerer L. 2006. Neonatal-onset multisystem inflammatory disease (NOMID) due to a novel S331R mutation of the CIAS1 gene and response to interleukin-1 receptor antagonist treatment. Am J Med Genet A 140:883–886. [PubMed]
81. Koné-Paut I, Sanchez E, Le Quellec A, Manna R, Touitou I. 2007. Autoinflammatory gene mutations in Behçet’s disease. Ann Rheum Dis 66:832–834. [PubMed]
82. McDermott MF, Aksentijevich I. 2002. The autoinflammatory syndromes. Curr Opin Allergy Clin Immunol 2:511–516. [PubMed]
83. Robbins GR, Wen H, Ting JP. 2014. Inflammasomes and metabolic disorders: old genes in modern diseases. Mol Cell 54:297–308. [PubMed]
84. Stojanov S, Kastner DL. 2005. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol 17:586–599. [PubMed]
85. Dodé C, Le Dû N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, Meyrier A, Watts RA, Scott DG, Nicholls A, Granel B, Frances C, Garcier F, Edery P, Boulinguez S, Domergues JP, Delpech M, Grateau G. 2002. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet 70:1498–1506. [PubMed]
86. Hoffman HM, Gregory SG, Mueller JL, Tresierras M, Broide DH, Wanderer AA, Kolodner RD. 2003. Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P. Hum Genet 112:209–216. [PubMed]
87. Ting JP, Kastner DL, Hoffman HM. 2006. CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 6:183–195. [PubMed]
88. Dinarello CA, van der Meer JW. 2013. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 25:469–484. [PubMed]
89. Dinarello CA, Simon A, van der Meer JW. 2012. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 11:633–652. [PubMed]
90. Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O’Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, Cole JL, Paul SM, Hawkins PN, Pham TH, Snyder C, Wesley RA, Hoffmann SC, Holland SM, Butman JA, Kastner DL. 2006. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N Engl J Med 355:581–592. [PubMed]
91. Cai X, Chen J, Xu H, Liu S, Jiang QX, Halfmann R, Chen ZJ. 2014. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156:1207–1222. [PubMed]
92. Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, Vos MR, Schröder GF, Fitzgerald KA, Wu H, Egelman EH. 2014. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156:1193–1206. [PubMed]
93. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A. 2006. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nat Immunol 7:569–575. [PubMed]
94. Amer A, Franchi L, Kanneganti TD, Body-Malapel M, Ozören N, Brady G, Meshinchi S, Jagirdar R, Gewirtz A, Akira S, Núñez G. 2006. Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf. J Biol Chem 281:35217–35223. [PubMed]
95. Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Nuñez G. 2007. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog 3:e111. doi:10.1371/journal.ppat.0030111.
96. Hu Z, Yan C, Liu P, Huang Z, Ma R, Zhang C, Wang R, Zhang Y, Martinon F, Miao D, Deng H, Wang J, Chang J, Chai J. 2013. Crystal structure of NLRC4 reveals its autoinhibition mechanism. Science 341:172–175. [PubMed]
97. Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES. 2001. Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J Biol Chem 276:28309–28313. [PubMed]
98. Geddes BJ, Wang L, Huang WJ, Lavellee M, Manji GA, Brown M, Jurman M, Cao J, Morgenstern J, Merriam S, Glucksmann MA, DiStefano PS, Bertin J. 2001. Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. Biochem Biophys Res Commun 284:77–82. [PubMed]
99. Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozören N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Núñez G. 2006. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages. Nat Immunol 7:576–582. [PubMed]
100. Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. 2007. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J Exp Med 204:3235–3245. [PubMed]
101. Yang J, Zhao Y, Shi J, Shao F. 2013. Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation. Proc Natl Acad Sci U S A 110:14408–14413. [PubMed]
102. Kofoed EM, Vance RE. 2011. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477:592–595. [PubMed]
103. Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, Liu L, Shao F. 2011. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477:596–600. [PubMed]
104. Rayamajhi M, Zak DE, Chavarria-Smith J, Vance RE, Miao EA. 2013. Cutting edge: mouse NAIP1 detects the type III secretion system needle protein. J Immunol 191:3986–3989. [PubMed]
105. Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Mariathasan S, Dixit VM, Flavell RA, Dietrich WF, Roy CR. 2006. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 7:318–325. [PubMed]
106. Lightfield KL, Persson J, Brubaker SW, Witte CE, von Moltke J, Dunipace EA, Henry T, Sun YH, Cado D, Dietrich WF, Monack DM, Tsolis RM, Vance RE. 2008. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat Immunol 9:1171–1178. [PubMed]
107. 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. [PubMed]
108. Rauch I, Tenthorey JL, Nichols RD, Al Moussawi K, Kang JJ, Kang C, Kazmierczak BI, Vance RE. 2016. NAIP proteins are required for cytosolic detection of specific bacterial ligands in vivo. J Exp Med 213:657–665. [PubMed]
109. Zhao Y, Shi J, Shi X, Wang Y, Wang F, Shao F. 2016. Genetic functions of the NAIP family of inflammasome receptors for bacterial ligands in mice. J Exp Med 213:647–656. [PubMed]
110. Diebolder CA, Halff EF, Koster AJ, Huizinga EG, Koning RI. 2015. Cryoelectron tomography of the NAIP5/NLRC4 inflammasome: implications for NLR activation. Structure 23:2349–2357. [PubMed]
111. Hu Z, Zhou Q, Zhang C, Fan S, Cheng W, Zhao Y, Shao F, Wang HW, Sui SF, Chai J. 2015. Structural and biochemical basis for induced self-propagation of NLRC4. Science 350:399–404. [PubMed]
112. Zhang L, Chen S, Ruan J, Wu J, Tong AB, Yin Q, Li Y, David L, Lu A, Wang WL, Marks C, Ouyang Q, Zhang X, Mao Y, Wu H. 2015. Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization. Science 350:404–409. [PubMed]
113. Sellin ME, Müller AA, Felmy B, Dolowschiak T, Diard M, Tardivel A, Maslowski KM, Hardt WD. 2014. Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe 16:237–248. [PubMed]
114. Maier JK, Lahoua Z, Gendron NH, Fetni R, Johnston A, Davoodi J, Rasper D, Roy S, Slack RS, Nicholson DW, MacKenzie AE. 2002. The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7. J Neurosci 22:2035–2043. [PubMed]
115. Davoodi J, Ghahremani MH, Es-Haghi A, Mohammad-Gholi A, Mackenzie A. 2010. Neuronal apoptosis inhibitory protein, NAIP, is an inhibitor of procaspase-9. Int J Biochem Cell Biol 42:958–964. [PubMed]
116. Vinzing M, Eitel J, Lippmann J, Hocke AC, Zahlten J, Slevogt H, N’guessan PD, Günther S, Schmeck B, Hippenstiel S, Flieger A, Suttorp N, Opitz B. 2008. NAIP and Ipaf control Legionella pneumophila replication in human cells. J Immunol 180:6808–6815. [PubMed]
117. Roy N, Mahadevan MS, McLean M, Shutter G, Yaraghi Z, Farahani R, Baird S, Besner-Johnston A, Lefebvre C, Kang X, Salih M, Aubry H, Tamai K, Guan X, Ioannou P, Crawford TO, de Jong PJ, Surh L, Ikeda JE, Korneluk RG, MacKenzie A. 1995. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80:167–178.
118. Wirth B, Hahnen E, Morgan K, DiDonato CJ, Dadze A, Rudnik-Schöneborn S, Simard LR, Zerres K, Burghes AH. 1995. Allelic association and deletions in autosomal recessive proximal spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs. Hum Mol Genet 4:1273–1284. [PubMed]
119. Theodorou L, Nicolaou P, Koutsou P, Georghiou A, Anastasiadou V, Tanteles G, Kyriakides T, Zamba-Papanicolaou E, Christodoulou K. 2015. Genetic findings of Cypriot spinal muscular atrophy patients. Neurol Sci 36:1829–1834. [PubMed]
120. Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, DiMattia MA, Zaal KJ, Sanchez GA, Kim H, Chapelle D, Plass N, Huang Y, Villarino AV, Biancotto A, Fleisher TA, Duncan JA, O’Shea JJ, Benseler S, Grom A, Deng Z, Laxer RM, Goldbach-Mansky R. 2014. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet 46:1140–1146. [PubMed]
121. Grenier JM, Wang L, Manji GA, Huang WJ, Al-Garawi A, Kelly R, Carlson A, Merriam S, Lora JM, Briskin M, DiStefano PS, Bertin J. 2002. Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-κB and caspase-1. FEBS Lett 530:73–78.
122. Anand PK, Kanneganti TD. 2012. Targeting NLRP6 to enhance immunity against bacterial infections. Future Microbiol 7:1239–1242. [PubMed]
123. Anand PK, Kanneganti TD. 2013. NLRP6 in infection and inflammation. Microbes Infect 15:661–668. [PubMed]
124. Anand PK, Malireddi RK, Lukens JR, Vogel P, Bertin J, Lamkanfi M, Kanneganti TD. 2012. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488:389–393. [PubMed]
125. Chen GY, Liu M, Wang F, Bertin J, Núñez G. 2011. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J Immunol 186:7187–7194. [PubMed]
126. Normand S, Delanoye-Crespin A, Bressenot A, Huot L, Grandjean T, Peyrin-Biroulet L, Lemoine Y, Hot D, Chamaillard M. 2011. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc Natl Acad Sci U S A 108:9601–9606. [PubMed]
127. Kempster SL, Belteki G, Forhead AJ, Fowden AL, Catalano RD, Lam BY, McFarlane I, Charnock-Jones DS, Smith GC. 2011. Developmental control of the Nlrp6 inflammasome and a substrate, IL-18, in mammalian intestine. Am J Physiol Gastrointest Liver Physiol 300:G253–G263. [PubMed]
128. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, Flavell RA. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745–757. [PubMed]
129. Seregin SS, Golovchenko N, Schaf B, Chen J, Eaton KA, Chen GY. 2016. NLRP6 function in inflammatory monocytes reduces susceptibility to chemically induced intestinal injury. Mucosal Immunol doi:10.1038/mi.2016.55. [PubMed]
130. Levy M, Thaiss CA, Zeevi D, Dohnalová L, Zilberman-Schapira G, Mahdi JA, David E, Savidor A, Korem T, Herzig Y, Pevsner-Fischer M, Shapiro H, Christ A, Harmelin A, Halpern Z, Latz E, Flavell RA, Amit I, Segal E, Elinav E. 2015. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163:1428–1443. [PubMed]
131. Wang P, Zhu S, Yang L, Cui S, Pan W, Jackson R, Zheng Y, Rongvaux A, Sun Q, Yang G, Gao S, Lin R, You F, Flavell R, Fikrig E. 2015. Nlrp6 regulates intestinal antiviral innate immunity. Science 350:826–830. [PubMed]
132. Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang JP, Brown EM, Frankel G, Levy M, Katz MN, Philbrick WM, Elinav E, Finlay BB, Flavell RA. 2014. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156:1045–1059. [PubMed]
133. Birchenough GM, Nyström EE, Johansson ME, Hansson GC. 2016. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science 352:1535–1542. [PubMed]
134. Triantafilou K, Kar S, van Kuppeveld FJ, Triantafilou M. 2013. Rhinovirus-induced calcium flux triggers NLRP3 and NLRC5 activation in bronchial cells. Am J Respir Cell Mol Biol 49:923–934. [PubMed]
135. Yao Y, Wang Y, Chen F, Huang Y, Zhu S, Leng Q, Wang H, Shi Y, Qian Y. 2012. NLRC5 regulates MHC class I antigen presentation in host defense against intracellular pathogens. Cell Res 22:836–847. [PubMed]
136. Pinheiro AS, Proell M, Eibl C, Page R, Schwarzenbacher R, Peti W. 2010. Three-dimensional structure of the NLRP7 pyrin domain: insight into pyrin-pyrin-mediated effector domain signaling in innate immunity. J Biol Chem 285:27402–27410. [PubMed]
137. Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, de Almeida L, Rojanasakul Y, Stehlik C. 2012. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 36:464–476. [PubMed]
138. Radian AD, Khare S, Chu LH, Dorfleutner A, Stehlik C. 2015. ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides. Mol Immunol 67(2 Pt B) :294–302. [PubMed]
139. Slim R, Wallace EP. 2013. NLRP7 and the genetics of hydatidiform moles: recent advances and new challenges. Front Immunol 4:242. doi:10.3389/fimmu.2013.00242. [PubMed]
140. Singer H, Biswas A, Nuesgen N, Oldenburg J, El-Maarri O. 2015. NLRP7, involved in hydatidiform molar pregnancy (HYDM1), interacts with the transcriptional repressor ZBTB16. PLoS One 10:e0130416. doi:10.1371/journal.pone.0130416. [PubMed]
141. Lich JD, Williams KL, Moore CB, Arthur JC, Davis BK, Taxman DJ, Ting JP. 2007. Monarch-1 suppresses non-canonical NF-κB activation and p52-dependent chemokine expression in monocytes. J Immunol 178:1256–1260. [PubMed]
142. Williams KL, Lich JD, Duncan JA, Reed W, Rallabhandi P, Moore C, Kurtz S, Coffield VM, Accavitti-Loper MA, Su L, Vogel SN, Braunstein M, Ting JP. 2005. The CATERPILLER protein Monarch-1 is an antagonist of Toll-like receptor-, tumor necrosis factor α-, and Mycobacterium tuberculosis-induced pro-inflammatory signals. J Biol Chem 280:39914–39924. [PubMed]
143. Pinheiro AS, Eibl C, Ekman-Vural Z, Schwarzenbacher R, Peti W. 2011. The NLRP12 pyrin domain: structure, dynamics, and functional insights. J Mol Biol 413:790–803. [PubMed]
144. Williams KL, Taxman DJ, Linhoff MW, Reed W, Ting JP. 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 170:5354–5358. [PubMed]
145. Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S, Lora JM, Geddes BJ, Briskin M, DiStefano PS, Bertin J. 2002. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-κB and caspase-1-dependent cytokine processing. J Biol Chem 277:29874–29880. [PubMed]
146. Ataide MA, Andrade WA, Zamboni DS, Wang D, Souza MC, Franklin BS, Elian S, Martins FS, Pereira D, Reed G, Fitzgerald KA, Golenbock DT, Gazzinelli RT. 2014. Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathog 10:e1003885. doi:10.1371/journal.ppat.1003885.
147. Vladimer GI, Weng D, Paquette SW, Vanaja SK, Rathinam VA, Aune MH, Conlon JE, Burbage JJ, Proulx MK, Liu Q, Reed G, Mecsas JC, Iwakura Y, Bertin J, Goguen JD, Fitzgerald KA, Lien E. 2012. The NLRP12 inflammasome recognizes Yersinia pestis. Immunity 37:96–107. [PubMed]
148. Zaki MH, Vogel P, Malireddi RK, Body-Malapel M, Anand PK, Bertin J, Green DR, Lamkanfi M, Kanneganti TD. 2011. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 20:649–660. [PubMed]
149. Allen IC, Wilson JE, Schneider M, Lich JD, Roberts RA, Arthur JC, Woodford RM, Davis BK, Uronis JM, Herfarth HH, Jobin C, Rogers AB, Ting JP. 2012. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling. Immunity 36:742–754. [PubMed]
150. Zaki MH, Man SM, Vogel P, Lamkanfi M, Kanneganti TD. 2014. Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection. Proc Natl Acad Sci U S A 111:385–390. [PubMed]
151. Allen IC, McElvania-TeKippe E, Wilson JE, Lich JD, Arthur JC, Sullivan JT, Braunstein M, Ting JP. 2013. Characterization of NLRP12 during the in vivo host immune response to Klebsiella pneumoniae and Mycobacterium tuberculosis. PLoS One 8:e60842. doi:10.1371/journal.pone.0060842.
152. Jéru I, Duquesnoy P, Fernandes-Alnemri T, Cochet E, Yu JW, Lackmy-Port-Lis M, Grimprel E, Landman-Parker J, Hentgen V, Marlin S, McElreavey K, Sarkisian T, Grateau G, Alnemri ES, Amselem S. 2008. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A 105:1614–1619. [PubMed]
153. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458:514–518. [PubMed]
154. Jones JW, Kayagaki N, Broz P, Henry T, Newton K, O’Rourke K, Chan S, Dong J, Qu Y, Roose-Girma M, Dixit VM, Monack DM. 2010. Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis. Proc Natl Acad Sci U S A 107:9771–9776. [PubMed]
155. Sagulenko V, Thygesen SJ, Sester DP, Idris A, Cridland JA, Vajjhala PR, Roberts TL, Schroder K, Vince JE, Hill JM, Silke J, Stacey KJ. 2013. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ 20:1149–1160. [PubMed]
156. Warren SE, Armstrong A, Hamilton MK, Mao DP, Leaf IA, Miao EA, Aderem A. 2010. Cutting edge: cytosolic bacterial DNA activates the inflammasome via Aim2. J Immunol 185:818–821. [PubMed]
157. DeYoung KL, Ray ME, Su YA, Anzick SL, Johnstone RW, Trapani JA, Meltzer PS, Trent JM. 1997. Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene 15:453–457. [PubMed]
158. Bürckstümmer T, Baumann C, Blüml S, Dixit E, Dürnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL, Superti-Furga G. 2009. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol 10:266–272. [PubMed]
159. Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S, Wu J, Datta P, McCormick M, Huang L, McDermott E, Eisenlohr L, Landel CP, Alnemri ES. 2010. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat Immunol 11:385–393. [PubMed]
160. Jin T, Perry A, Smith P, Jiang J, Xiao TS. 2013. Structure of the absent in melanoma 2 (AIM2) pyrin domain provides insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. J Biol Chem 288:13225–13235. [PubMed]
161. Wang LJ, Huang HY, Huang MP, Liou W, Chang YT, Wu CC, Ojcius DM, Chang YS. 2014. The microtubule-associated protein EB1 links AIM2 inflammasomes with autophagy-dependent secretion. J Biol Chem 289:29322–29333. [PubMed]
162. Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, Vanaja SK, Monks BG, Ganesan S, Latz E, Hornung V, Vogel SN, Szomolanyi-Tsuda E, Fitzgerald KA. 2010. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11:395–402. [PubMed]
163. Saiga H, Kitada S, Shimada Y, Kamiyama N, Okuyama M, Makino M, Yamamoto M, Takeda K. 2012. Critical role of AIM2 in Mycobacterium tuberculosis infection. Int Immunol 24:637–644. [PubMed]
164. Sauer JD, Witte CE, Zemansky J, Hanson B, Lauer P, Portnoy DA. 2010. Listeria monocytogenes that lyse in the macrophage cytosol trigger AIM2-mediated pyroptosis. Cell Host Microbe 7:412–419. [PubMed]
165. Hanamsagar R, Aldrich A, Kielian T. 2014. Critical role for the AIM2 inflammasome during acute central nervous system bacterial infection. J Neurochem 129:704–711. [PubMed]
166. Man SM, Zhu Q, Zhu L, Liu Z, Karki R, Malik A, Sharma D, Li L, Malireddi RK, Gurung P, Neale G, Olsen SR, Carter RA, McGoldrick DJ, Wu G, Finkelstein D, Vogel P, Gilbertson RJ, Kanneganti TD. 2015. Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell 162:45–58. [PubMed]
167. Patsos G, Germann A, Gebert J, Dihlmann S. 2010. Restoration of absent in melanoma 2 (AIM2) induces G2/M cell cycle arrest and promotes invasion of colorectal cancer cells. Int J Cancer 126:1838–1849. [PubMed]
168. Wilson JE, Petrucelli AS, Chen L, Koblansky AA, Truax AD, Oyama Y, Rogers AB, Brickey WJ, Wang Y, Schneider M, Mühlbauer M, Chou WC, Barker BR, Jobin C, Allbritton NL, Ramsden DA, Davis BK, Ting JP. 2015. Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat Med 21:906–913. [PubMed]
169. Chen IF, Ou-Yang F, Hung JY, Liu JC, Wang H, Wang SC, Hou MF, Hortobagyi GN, Hung MC. 2006. AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model. Mol Cancer Ther 5:1–7. [PubMed]
170. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J, Lee WP, Roose-Girma M, Dixit VM. 2011. Non-canonical inflammasome activation targets caspase-11. Nature 479:117–121. [PubMed]
171. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA. 2013. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341:1250–1253. [PubMed]
172. Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszyński A, Forsberg LS, Carlson RW, Dixit VM. 2013. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341:1246–1249. [PubMed]
173. Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F. 2014. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514:187–192. [PubMed]
174. Zanoni I, Tan Y, Di Gioia M, Broggi A, Ruan J, Shi J, Donado CA, Shao F, Wu H, Springstead JR, Kagan JC. 2016. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352:1232–1236. [PubMed]
175. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM. 2015. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671. [PubMed]
176. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F. 2015. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660–665. [PubMed]
177. Viganò E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A. 2015. Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun 6:8761. doi:10.1038/ncomms9761. [PubMed]
178. Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C, Ting JP. 2010. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med 207:1045–1056. [PubMed]
179. Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD. 2010. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32:379–391. [PubMed]
180. Dupaul-Chicoine J, Arabzadeh A, Dagenais M, Douglas T, Champagne C, Morizot A, Rodrigue-Gervais IG, Breton V, Colpitts SL, Beauchemin N, Saleh M. 2015. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity 43:751–763. [PubMed]
181. Bauer C, Duewell P, Mayer C, Lehr HA, Fitzgerald KA, Dauer M, Tschopp J, Endres S, Latz E, Schnurr M. 2010. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 59:1192–1199. [PubMed]
182. Okamoto M, Liu W, Luo Y, Tanaka A, Cai X, Norris DA, Dinarello CA, Fujita M. 2010. Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1β. J Biol Chem 285:6477–6488. [PubMed]
183. Verma D, Bivik C, Farahani E, Synnerstad I, Fredrikson M, Enerbäck C, Rosdahl I, Söderkvist P. 2012. Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma. Pigment Cell Melanoma Res 25:506–513. [PubMed]
184. Xu Y, Li H, Chen W, Yao X, Xing Y, Wang X, Zhong J, Meng G. 2013. Mycoplasma hyorhinis activates the NLRP3 inflammasome and promotes migration and invasion of gastric cancer cells. PLoS One 8:e77955. doi:10.1371/journal.pone.0077955.
185. Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, Zhao W, Huai W, Guo P, Han L. 2014. Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression. Lab Invest 94:52–62. [PubMed]
186. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, Perfettini JL, Schlemmer F, Tasdemir E, Uhl M, Génin P, Civas A, Ryffel B, Kanellopoulos J, Tschopp J, André F, Lidereau R, McLaughlin NM, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L. 2009. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat Med 15:1170–1178. [PubMed]
187. van Deventer HW, Burgents JE, Wu QP, Woodford RM, Brickey WJ, Allen IC, McElvania-Tekippe E, Serody JS, Ting JP. 2010. The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells. Cancer Res 70:10161–10169. [PubMed]
188. Carmi Y, Dotan S, Rider P, Kaplanov I, White MR, Baron R, Abutbul S, Huszar M, Dinarello CA, Apte RN, Voronov E. 2013. The role of IL-1β in the early tumor cell-induced angiogenic response. J Immunol 190:3500–3509. [PubMed]
189. Tarassishin L, Lim J, Weatherly DB, Angeletti RH, Lee SC. 2014. Interleukin-1-induced changes in the glioblastoma secretome suggest its role in tumor progression. J Proteomics 99:152–168. [PubMed]
190. Hu B, Elinav E, Huber S, Booth CJ, Strowig T, Jin C, Eisenbarth SC, Flavell RA. 2010. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc Natl Acad Sci U S A 107:21635–21640. [PubMed]
191. Chen YK, Huse SS, Lin LM. 2011. Expression of inhibitor of apoptosis family proteins in human oral squamous cell carcinogenesis. Head Neck 33:985–998. [PubMed]
192. Choi J, Hwang YK, Choi YJ, Yoo KE, Kim JH, Nam SJ, Yang JH, Lee SJ, Yoo KH, Sung KW, Koo HH, Im YH. 2007. Neuronal apoptosis inhibitory protein is overexpressed in patients with unfavorable prognostic factors in breast cancer. J Korean Med Sci 22(Suppl) :S17–S23. [PubMed]
193. Krajewska M, Krajewski S, Banares S, Huang X, Turner B, Bubendorf L, Kallioniemi OP, Shabaik A, Vitiello A, Peehl D, Gao GJ, Reed JC. 2003. Elevated expression of inhibitor of apoptosis proteins in prostate cancer. Clin Cancer Res 9:4914–4925. [PubMed]
194. McConnell BB, Vertino PM. 2004. TMS1/ASC: the cancer connection. Apoptosis 9:5–18. [PubMed]
195. Levine JJ, Stimson-Crider KM, Vertino PM. 2003. Effects of methylation on expression of TMS1/ASC in human breast cancer cells. Oncogene 22:3475–3488. [PubMed]
196. Yokoyama T, Sagara J, Guan X, Masumoto J, Takeoka M, Komiyama Y, Miyata K, Higuchi K, Taniguchi S. 2003. Methylation of ASC/TMS1, a proapoptotic gene responsible for activating procaspase-1, in human colorectal cancer. Cancer Lett 202:101–108. [PubMed]
197. Das PM, Ramachandran K, Vanwert J, Ferdinand L, Gopisetty G, Reis IM, Singal R. 2006. Methylation mediated silencing of TMS1/ASC gene in prostate cancer. Mol Cancer 5:28. doi:10.1186/1476-4598-5-28. [PubMed]
198. Machida EO, Brock MV, Hooker CM, Nakayama J, Ishida A, Amano J, Picchi MA, Belinsky SA, Herman JG, Taniguchi S, Baylin SB. 2006. Hypermethylation of ASC/TMS1 is a sputum marker for late-stage lung cancer. Cancer Res 66:6210–6218. [PubMed]
199. Stone AR, Bobo W, Brat DJ, Devi NS, Van Meir EG, Vertino PM. 2004. Aberrant methylation and down-regulation of TMS1/ASC in human glioblastoma. Am J Pathol 165:1151–1161. [PubMed]
200. Liu W, Luo Y, Dunn JH, Norris DA, Dinarello CA, Fujita M. 2013. Dual role of apoptosis-associated speck-like protein containing a CARD (ASC) in tumorigenesis of human melanoma. J Invest Dermatol 133:518–527. [PubMed]
201. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. 2013. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678. [PubMed]
202. Gris D, Ye Z, Iocca HA, Wen H, Craven RR, Gris P, Huang M, Schneider M, Miller SD, Ting JP. 2010. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J Immunol 185:974–981. [PubMed]
203. Jha S, Ting JP. 2009. Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases. J Immunol 183:7623–7629. [PubMed]
204. Inoue M, Williams KL, Oliver T, Vandenabeele P, Rajan JV, Miao EA, Shinohara ML. 2012. Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome. Sci Signal 5:ra38. doi:10.1126/scisignal.2002767.
205. Kimkong I, Avihingsanon Y, Hirankarn N. 2009. Expression profile of HIN200 in leukocytes and renal biopsy of SLE patients by real-time RT-PCR. Lupus 18:1066–1072. [PubMed]
206. Wozniacka A, Lesiak A, Narbutt J, McCauliffe DP, Sysa-Jedrzejowska A. 2006. Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients. Lupus 15:268–275. [PubMed]
Loading

Article metrics loading...

/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016
2017-01-20
2019-08-25

Abstract:

The inflammasome is a large multimeric protein complex comprising an effector protein that demonstrates specificity for a variety of activators or ligands; an adaptor molecule; and procaspase-1, which is converted to caspase-1 upon inflammasome activation. Inflammasomes are expressed primarily by myeloid cells and are located within the cell. The macromolecular inflammasome structure can be visualized by cryo-electron microscopy. This complex has been found to play a role in a variety of disease models in mice, and several have been genetically linked to human diseases. In most cases, the effector protein is a member of the NLR (nucleotide-binding domain leucine-rich repeat-containing) or NOD (nucleotide oligomerization domain)-like receptor protein family. However, other effectors have also been described, with the most notable being AIM-2 (absent in melanoma 2), which recognizes DNA to elicit inflammasome function. This review will focus on the role of the inflammasome in myeloid cells and its role in health and disease.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Inflammasomes in Myeloid Cells: Warriors Within
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-1,webId=/content/author/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-1,properties={foaf_givenname=Sushmita, foaf_name=Sushmita Jha, foaf_surname=Jha, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-2,webId=/content/author/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-2,properties={foaf_givenname=W. June, foaf_name=W. June Brickey, foaf_surname=Brickey, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-aff2]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-3,webId=/content/author/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-3,properties={foaf_givenname=Jenny Pan-Yun, foaf_name=Jenny Pan-Yun Ting, foaf_surname=Ting, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-aff4],com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016-aff3]]}]]
Citation: Jha S, Brickey W, Ting J. 2017. Inflammasomes in myeloid cells: warriors within. microbiolspec 5(1): doi:10.1128/microbiolspec.MCHD-0049-2016
/content/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016.fig1
FIGURE 1
NLRs function in healthy and dysregulated disease states in the human body.
microbiolspec/5/1/MCHD-0049-2016-fig1_thmb.gif
microbiolspec/5/1/MCHD-0049-2016-fig1.gif
Image of FIGURE 1
FIGURE 1

NLRs function in healthy and dysregulated disease states in the human body.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0049-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016.fig2
FIGURE 2
NLRs have a conserved tripartite structure with an N-terminal effector domain, a central NBD, and C-terminal LRRs. The effector domains of NLRs may include acidic transactivation domain (AD), baculoviral inhibitory repeat (BIR)-like domain, caspase-recruitment domain (CARD), pyrin domain, or domain of unknown function (X). In general, NLRP1, NLRP3, NLRP6, NLRP7, NLRC4, NAIP, and AIM2 are known to form inflammasomes, while CIITA, NOD1, NOD2, NLRC3, NLRC5, NLRX1, NLRP10, and NLRP12 do not.
microbiolspec/5/1/MCHD-0049-2016-fig2_thmb.gif
microbiolspec/5/1/MCHD-0049-2016-fig2.gif
Image of FIGURE 2
FIGURE 2

NLRs have a conserved tripartite structure with an N-terminal effector domain, a central NBD, and C-terminal LRRs. The effector domains of NLRs may include acidic transactivation domain (AD), baculoviral inhibitory repeat (BIR)-like domain, caspase-recruitment domain (CARD), pyrin domain, or domain of unknown function (X). In general, NLRP1, NLRP3, NLRP6, NLRP7, NLRC4, NAIP, and AIM2 are known to form inflammasomes, while CIITA, NOD1, NOD2, NLRC3, NLRC5, NLRX1, NLRP10, and NLRP12 do not.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0049-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/microbiolspec/10.1128/microbiolspec.MCHD-0049-2016.fig3
FIGURE 3
The NLRP3 inflammasome is activated in response to several PAMPs and DAMPs, including but not limited to nucleic acids, LPS, lipooligosaccharide (LOS), MDP, ATP, uric acid crystals, hyaluronan sulfate, heparan sulfate, β-amyloid, asbestos, and silica. NLRP3 inflammasome formation is a two-signal process. The first signal involves priming: LPS engagement of TLR4 leads to NF-κB activation, causing increased expression of NLRP3 and IL-1β (step 1). NLRP3 forms a multiprotein inflammasome complex with the adaptor ASC and procaspase-1. NLRP3 and ASC undergo deubiquitination prior to inflammasome assembly. After priming, canonical inflammasome activation requires a second signal. The second signal may be the release into the cytoplasm of mitochondrial factors such as ROS, mitochondrial DNA (mtDNA), or cardiolipin (step 2), potassium efflux (step 3), or lysosomal cathepsin release (step 4). After receiving the second signal, NLRP3 recruits ASC via pyrin-pyrin interactions. ASC utilizes its CARD domain to recruit procaspase-1 by CARD-CARD interactions, thus leading to processing of procaspase-1 to active caspase-1 (step 5). In turn, caspase-1 is critical for the processing and release of IL-1β and IL-18.
microbiolspec/5/1/MCHD-0049-2016-fig3_thmb.gif
microbiolspec/5/1/MCHD-0049-2016-fig3.gif
Image of FIGURE 3
FIGURE 3

The NLRP3 inflammasome is activated in response to several PAMPs and DAMPs, including but not limited to nucleic acids, LPS, lipooligosaccharide (LOS), MDP, ATP, uric acid crystals, hyaluronan sulfate, heparan sulfate, β-amyloid, asbestos, and silica. NLRP3 inflammasome formation is a two-signal process. The first signal involves priming: LPS engagement of TLR4 leads to NF-κB activation, causing increased expression of NLRP3 and IL-1β (step 1). NLRP3 forms a multiprotein inflammasome complex with the adaptor ASC and procaspase-1. NLRP3 and ASC undergo deubiquitination prior to inflammasome assembly. After priming, canonical inflammasome activation requires a second signal. The second signal may be the release into the cytoplasm of mitochondrial factors such as ROS, mitochondrial DNA (mtDNA), or cardiolipin (step 2), potassium efflux (step 3), or lysosomal cathepsin release (step 4). After receiving the second signal, NLRP3 recruits ASC via pyrin-pyrin interactions. ASC utilizes its CARD domain to recruit procaspase-1 by CARD-CARD interactions, thus leading to processing of procaspase-1 to active caspase-1 (step 5). In turn, caspase-1 is critical for the processing and release of IL-1β and IL-18.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0049-2016
Permissions and Reprints Request Permissions
Download as Powerpoint

Supplemental Material

No supplementary material available for this content.

Back to top
This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error