Skip to main content

Advertisement

Log in

The intersection of cell death and inflammasome activation

  • Multi-author review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Inflammasomes sense cellular danger to activate the cysteine-aspartic protease caspase-1, which processes precursor interleukin-1β (IL-1β) and IL-18 into their mature bioactive fragments. In addition, activated caspase-1 or the related inflammatory caspase, caspase-11, can cleave gasdermin D to induce a lytic cell death, termed pyroptosis. The intertwining of IL-1β activation and cell death is further highlighted by research showing that the extrinsic apoptotic caspase, caspase-8, may, like caspase-1, directly process IL-1β, activate the NLRP3 inflammasome itself, or bind to inflammasome complexes to induce apoptotic cell death. Similarly, RIPK3- and MLKL-dependent necroptotic signaling can activate the NLRP3 inflammasome to drive IL-1β inflammatory responses in vivo. Here, we review the mechanisms by which cell death signaling activates inflammasomes to initiate IL-1β-driven inflammation, and highlight the clinical relevance of these findings to heritable autoinflammatory diseases. We also discuss whether the act of cell death can be separated from IL-1β secretion and evaluate studies suggesting that several cell death regulatory proteins can directly interact with, and modulate the function of, inflammasome and IL-1β containing protein complexes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Becker CE, O’Neill LA (2007) Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs. Semin Immunopathol 29(3):239–248. doi:10.1007/s00281-007-0081-4

    Article  CAS  PubMed  Google Scholar 

  2. Menu P, Vince JE (2011) The NLRP3 inflammasome in health and disease: the good, the bad and the ugly. Clin Exp Immunol 166(1):1–15. doi:10.1111/j.1365-2249.2011.04440.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Silke J, Rickard JA, Gerlic M (2015) The diverse role of RIP kinases in necroptosis and inflammation. Nat Immunol 16(7):689–697

    Article  CAS  PubMed  Google Scholar 

  4. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10(2):417–426. pii: S1097276502005993

  5. Schroder K, Tschopp J (2010) The inflammasomes. Cell 140(6):821–832. doi:10.1016/j.cell.2010.01.040

    Article  CAS  PubMed  Google Scholar 

  6. Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E, Shen Y, Mizuguchi J, Schweighoffer E, Tybulewicz V, Mitsuyama M (2013) Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol 14(12):1247–1255. doi:10.1038/ni.2749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, Vos MR, Schroder GF, Fitzgerald KA, Wu H, Egelman EH (2014) Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156(6):1193–1206. doi:10.1016/j.cell.2014.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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(6):1207–1222. doi:10.1016/j.cell.2014.01.063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chae JJ, Cho YH, Lee GS, Cheng J, Liu PP, Feigenbaum L, Katz SI, Kastner DL (2011) Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice. Immunity 34(5):755–768. doi:10.1016/j.immuni.2011.02.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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(6):1009–1023. doi:10.1016/j.immuni.2012.08.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Neven B, Prieur A-M, Quartier dit Maire P, Medscape (2008) Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol 4(9):481–489. doi:10.1038/ncprheum0874

    Article  CAS  PubMed  Google Scholar 

  12. 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(10):1140–1146. doi:10.1038/ng.3089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP (2014) Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet 46(10):1135–1139. doi:10.1038/ng.3066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lawlor KE, Vince JE (2014) Ambiguities in NLRP3 inflammasome regulation: is there a role for mitochondria? Biochim Biophys Acta 1840(4):1433–1440. doi:10.1016/j.bbagen.2013.08.014

    Google Scholar 

  15. Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, Nunez G (2013) K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38(6):1142–1153. doi:10.1016/j.immuni.2013.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Allam R, Lawlor KE, Yu EC, Mildenhall AL, Moujalled DM, Lewis RS, Ke F, Mason KD, White MJ, Stacey KJ, Strasser A, O’Reilly LA, Alexander W, Kile BT, Vaux DL, Vince JE (2014) Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep 15(9):982–990. doi:10.15252/embr.201438463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hornung V, Latz E (2010) Critical functions of priming and lysosomal damage for NLRP3 activation. Eur J Immunol 40(3):620–623. doi:10.1002/eji.200940185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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(7081):228–232. doi:10.1038/nature04515

    Article  CAS  PubMed  Google Scholar 

  19. Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469(7329):221–225. doi:10.1038/nature09663

    Article  CAS  PubMed  Google Scholar 

  20. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12(3):222–230. doi:10.1038/ni.1980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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(3):401–414. doi:10.1016/j.immuni.2012.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, Eisenbarth SC, Nauseef WM, Cassel SL, Sutterwala FS (2013) Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 39(2):311–323. doi:10.1016/j.immuni.2013.08.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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(7427):123–127. doi:10.1038/nature11588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464(7293):1357–1361. doi:1310.1038/nature08938

  25. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440(7081):237–241. doi:10.1038/nature04516

    Article  CAS  PubMed  Google Scholar 

  26. 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, Nunez 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-1beta in type 2 diabetes. Nat Immunol 11(10):897–904. doi:10.1038/ni.1935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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(2), pp. 179–188, doi:10.1038/nm.2279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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(5):408–415. doi:10.1038/ni.2022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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-beta. Nat Immunol 9(8):857–865. doi:10.1038/ni.1636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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(7434):674–678. doi:10.1038/nature11729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C (2015) NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol 6:262. doi:10.3389/fphar.2015.00262

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hersh D, Monack DM, Smith MR, Ghori N, Falkow S, Zychlinsky A (1999) The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc Natl Acad Sci USA 96(5):2396–2401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hilbi H, Moss JE, Hersh D, Chen Y, Arondel J, Banerjee S, Flavell RA, Yuan J, Sansonetti PJ, Zychlinsky A (1998) Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB. J Biol Chem 273(49):32895–32900

    Article  CAS  PubMed  Google Scholar 

  34. Chen Y, Smith MR, Thirumalai K, Zychlinsky A (1996) A bacterial invasin induces macrophage apoptosis by binding directly to ICE. EMBO J 15(15):3853–3860

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Croker BA, O’Donnell JA, Gerlic M (2014) Pyroptotic death storms and cytopenia. Curr Opin Immunol 26:128–137. doi:10.1016/j.coi.2013.1012.1002

    Article  CAS  PubMed  Google Scholar 

  36. Jorgensen I, Miao EA (2015) Pyroptotic cell death defends against intracellular pathogens. Immunol Rev 265(1), pp. 130–142, doi:10.1111/imr.12287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC (2014) Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 505(7484):509–514. doi:10.1038/nature12940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Brydges SD, Broderick L, McGeough MD, Pena CA, Mueller JL, Hoffman HM (2013) Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J Clin Invest 123(11):4695–4705. doi:10.1172/JCI71543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Keller M, Ruegg A, Werner S, Beer HD (2008) Active caspase-1 is a regulator of unconventional protein secretion. Cell 132(5):818–831. doi:10.1016/j.cell.2007.12.040

    Article  CAS  PubMed  Google Scholar 

  40. von Moltke J, Trinidad NJ, Moayeri M, Kintzer AF, Wang SB, van Rooijen N, Brown CR, Krantz BA, Leppla SH, Gronert K, Vance RE (2012) Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490(7418):107–111. doi:10.1038/nature11351

    Article  CAS  Google Scholar 

  41. 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(7521):187–192. doi:10.1038/nature13683

    CAS  PubMed  Google Scholar 

  42. Aachoui Y, Leaf IA, Hagar JA, Fontana MF, Campos CG, Zak DE, Tan MH, Cotter PA, Vance RE, Aderem A, Miao EA (2013) Caspase-11 protects against bacteria that escape the vacuole. Science 339(6122):975–978. doi:10.1126/science.1230751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszynski A, Forsberg LS, Carlson RW, Dixit VM (2013) Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science. doi:10.1126/science.1240248

    PubMed  Google Scholar 

  44. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA (2013) Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341(6151):1250–1253. doi:10.1126/science.1240988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ruhl S, Broz P (2015) Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux. Eur J Immunol 45(10):2927–2936. doi:10.1002/eji.201545772

    Article  PubMed  CAS  Google Scholar 

  46. Baker PJ, Boucher D, Bierschenk D, Tebartz C, Whitney PG, D’Silva DB, Tanzer MC, Monteleone M, Robertson AA, Cooper MA, Alvarez-Diaz S, Herold MJ, Bedoui S, Schroder K, Masters SL (2015) NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5. Eur J Immunol 45(10):2918–2926. doi:10.1002/eji.201545655

    Article  CAS  PubMed  Google Scholar 

  47. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J, Lee WP, Roose-Girma M, Dixit VM (2011) Non-canonical inflammasome activation targets caspase-11. Nature 479(7371):117–121

    Article  CAS  PubMed  Google Scholar 

  48. He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J (2015) Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res 25(12):1285–1298. doi:10.1038/cr.2015.139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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(7575):660–665. doi:10.1038/nature15514

    Article  CAS  PubMed  Google Scholar 

  50. 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(7575):666–671. doi:10.1038/nature15541

    Article  CAS  PubMed  Google Scholar 

  51. Yang D, He Y, Munoz-Planillo R, Liu Q, Nunez G (2015) Caspase-11 requires the pannexin-1 channel and the purinergic P2X7 pore to mediate pyroptosis and endotoxic shock. Immunity 43(5):923–932. doi:10.1016/j.immuni.2015.10.009

    Article  CAS  PubMed  Google Scholar 

  52. Monteleone M, Stow JL, Schroder K (2015) Mechanisms of unconventional secretion of IL-1 family cytokines. Cytokine 74(2):213–218. doi:10.1016/j.cyto.2015.03.022

    Article  CAS  PubMed  Google Scholar 

  53. Dupont N, Jiang S, Pilli M, Ornatowski W, Bhattacharya D, Deretic V (2011) Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1beta. EMBO J 30(23):4701–4711. doi:10.1038/emboj.2011.398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang M, Kenny SJ, Ge L, Xu K, Schekman R (2015) Translocation of interleukin-1beta into a vesicle intermediate in autophagy-mediated secretion. eLife. doi:10.7554/eLife.11205

    Google Scholar 

  55. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456(7219):264–268. doi:10.1038/nature07383

    Article  CAS  PubMed  Google Scholar 

  56. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH (2012) Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13(3):255–263. doi:10.1038/ni.2215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Liu T, Yamaguchi Y, Shirasaki Y, Shikada K, Yamagishi M, Hoshino K, Kaisho T, Takemoto K, Suzuki T, Kuranaga E, Ohara O, Miura M (2014) Single-cell imaging of caspase-1 dynamics reveals an all-or-none inflammasome signaling response. Cell Rep 8(4):974–982. doi:10.1016/j.celrep.2014.07.012

    Article  CAS  PubMed  Google Scholar 

  58. Shirasaki Y, Yamagishi M, Suzuki N, Izawa K, Nakahara A, Mizuno J, Shoji S, Heike T, Harada Y, Nishikomori R, Ohara O (2014) Real-time single-cell imaging of protein secretion. Sci Rep 4:4736. doi:10.1038/srep04736

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Cullen SP, Kearney CJ, Clancy DM, Martin SJ (2015) Diverse activators of the NLRP3 inflammasome promote IL-1beta secretion by triggering necrosis. Cell Rep 11(10):1535–1548. doi:10.1016/j.celrep.2015.05.003

    Article  CAS  PubMed  Google Scholar 

  60. Sagoo P, Garcia Z, Breart B, Lemaitre F, Michonneau D, Albert ML, Levy Y, Bousso P (2016) In vivo imaging of inflammasome activation reveals a subcapsular macrophage burst response that mobilizes innate and adaptive immunity. Nat Med 22(1):64–71. doi:10.1038/nm.4016

    Article  CAS  PubMed  Google Scholar 

  61. Chen KW, Gross CJ, Sotomayor FV, Stacey KJ, Tschopp J, Sweet MJ, Schroder K (2014) The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge. Cell Rep 8(2):570–582. doi:10.1016/j.celrep.2014.06.028

    Article  CAS  PubMed  Google Scholar 

  62. Karmakar M, Katsnelson M, Malak HA, Greene NG, Howell SJ, Hise AG, Camilli A, Kadioglu A, Dubyak GR, Pearlman E (2015) Neutrophil IL-1beta processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome and caspase-1 activation and is dependent on K + efflux. J Immunol 194(4):1763–1775. doi:10.4049/jimmunol.1401624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gross O, Yazdi AS, Thomas CJ, Masin M, Heinz LX, Guarda G, Quadroni M, Drexler SK, Tschopp J (2012) Inflammasome activators induce interleukin-1alpha secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 36(3):388–400. doi:10.1016/j.immuni.2012.01.018

    Article  CAS  PubMed  Google Scholar 

  64. Brough D, Rothwell NJ (2007) Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death. J Cell Sci 120(Pt 5):772–781

    Article  CAS  PubMed  Google Scholar 

  65. Silveira TN, Zamboni DS (2010) Pore formation triggered by Legionella spp. is an Nlrc4 inflammasome-dependent host cell response that precedes pyroptosis. Infect Immun 78(3):1403–1413. doi:10.1128/IAI.00905-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fink SL, Cookson BT (2006) Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol 8(11):1812–1825. doi:10.1111/j.1462-5822.2006.00751.x

    Article  CAS  PubMed  Google Scholar 

  67. Verhoef PA, Kertesy SB, Lundberg K, Kahlenberg JM, Dubyak GR (2005) Inhibitory effects of chloride on the activation of caspase-1, IL-1beta secretion, and cytolysis by the P2X7 receptor. J Immunol 175(11):7623–7634

    Article  CAS  PubMed  Google Scholar 

  68. Duong BH, Onizawa M, Oses-Prieto JA, Advincula R, Burlingame A, Malynn BA, Ma A (2015) A20 Restricts ubiquitination of pro-interleukin-1beta protein complexes and suppresses NLRP3 inflammasome activity. Immunity 42(1):55–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kang TB, Yang SH, Toth B, Kovalenko A, Wallach D (2013) Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38(1):27–40. doi:10.1016/j.immuni.2012.09.015

    Article  CAS  PubMed  Google Scholar 

  70. Silke J (2011) The regulation of TNF signalling: what a tangled web we weave. Curr Opin Immunol 23(5):620–626. doi:10.1016/j.coi.2011.08.002

    Article  CAS  PubMed  Google Scholar 

  71. Vince JE, Silke J (2009) Apoptosis: regulatory genes and disease. Wiley. doi:10.1002/9780470015902.a0006044.pub2

  72. Maelfait J, Vercammen E, Janssens S, Schotte P, Haegman M, Magez S, Beyaert R (2008) Stimulation of Toll-like receptor 3 and 4 induces interleukin-1beta maturation by caspase-8. J Exp Med 205(9):1967–1973. doi:10.1084/jem.20071632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O’Reilly L, Mason K, Gross O, Ma S, Guarda G, Anderton H, Castillo R, Hacker G, Silke J, Tschopp J (2012) Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36(2):215–227. doi:10.1016/j.immuni.2012.01.012

    Article  CAS  PubMed  Google Scholar 

  74. Stammler D, Eigenbrod T, Menz S, Frick JS, Sweet MJ, Shakespear MR, Jantsch J, Siegert I, Wolfle S, Langer JD, Oehme I, Schaefer L, Fischer A, Knievel J, Heeg K, Dalpke AH, Bode KA (2015) Inhibition of histone deacetylases permits lipopolysaccharide-mediated secretion of bioactive IL-1beta via a caspase-1-independent mechanism. J Immunol 195(11):5421–5431. doi:10.4049/jimmunol.1501195

    Article  CAS  PubMed  Google Scholar 

  75. Shenderov K, Riteau N, Yip R, Mayer-Barber KD, Oland S, Hieny S, Fitzgerald P, Oberst A, Dillon CP, Green DR, Cerundolo V, Sher A (2014) Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1beta in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway. J Immunol 192(5):2029–2033. doi:10.4049/jimmunol.1302549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Antonopoulos C, El Sanadi C, Kaiser WJ, Mocarski ES, Dubyak GR (2013) Proapoptotic chemotherapeutic drugs induce noncanonical processing and release of IL-1beta via caspase-8 in dendritic cells. J Immunol 191(9):4789–4803. doi:10.4049/jimmunol.1300645

    Article  CAS  PubMed  Google Scholar 

  77. Yabal M, Muller N, Adler H, Knies N, Gross CJ, Damgaard RB, Kanegane H, Ringelhan M, Kaufmann T, Heikenwalder M, Strasser A, Gross O, Ruland J, Peschel C, Gyrd-Hansen M, Jost PJ (2014) XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Rep 7(6):1796–1808. doi:10.1016/j.celrep.2014.05.008

    Article  CAS  PubMed  Google Scholar 

  78. Wu YH, Kuo WC, Wu YJ, Yang KT, Chen ST, Jiang ST, Gordy C, He YW, Lai MZ (2014) Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation. Cell Death Differ 21(3):451–461. doi:10.1038/cdd.2013.165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lawlor KE, Khan N, Mildenhall A, Gerlic M, Croker BA, D’Cruz AA, Hall C, Kaur Spall S, Anderton H, Masters SL, Rashidi M, Wicks IP, Alexander WS, Mitsuuchi Y, Benetatos CA, Condon SM, Wong WW, Silke J, Vaux DL, Vince JE (2015) RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat Commun 6:6282. doi:10.1038/ncomms7282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hedl M, Abraham C (2014) A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8-induced IL-1. Proc Natl Acad Sci USA 111(37):13451–13456. doi:10.1073/pnas.1404178111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tsutsui H, Kayagaki N, Kuida K, Nakano H, Hayashi N, Takeda K, Matsui K, Kashiwamura S, Hada T, Akira S, Yagita H, Okamura H, Nakanishi K (1999) Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice. Immunity 11(3):359–367 (pii: S1074-7613(00)80111-9 )

    Article  CAS  PubMed  Google Scholar 

  82. Moriwaki K, Bertin J, Gough PJ, Chan FK (2015) A RIPK3-caspase 8 complex mediates atypical pro-IL-1beta processing. J Immunol 194(4):1938–1944. doi:10.4049/jimmunol.1402167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gringhuis SI, Kaptein TM, Wevers BA, Theelen B, van der Vlist M, Boekhout T, Geijtenbeek TB (2012) Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1beta via a noncanonical caspase-8 inflammasome. Nat Immunol 13(3):246–254. doi:10.1038/ni.2222

    Article  CAS  PubMed  Google Scholar 

  84. Ganesan S, Rathinam VA, Bossaller L, Army K, Kaiser WJ, Mocarski ES, Dillon CP, Green DR, Mayadas TN, Levitz SM, Hise AG, Silverman N, Fitzgerald KA (2014) Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1beta production in response to beta-glucans and the fungal pathogen, Candida albicans. J Immunol 193(5), pp. 2519–2530, doi:10.4049/jimmunol.1400276

    Article  CAS  PubMed  Google Scholar 

  85. Chen M, Xing Y, Lu A, Fang W, Sun B, Chen C, Liao W, Meng G (2015) Internalized cryptococcus neoformans activates the canonical caspase-1 and the noncanonical caspase-8 inflammasomes. J Immunol 195(10):4962–4972. doi:10.4049/jimmunol.1500865

    Article  CAS  PubMed  Google Scholar 

  86. Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR (2011) Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature 471(7338):363–367. doi:10.1038/nature09852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471(7338):368–372. doi:10.1038/nature09857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sagulenko V, Lawlor KE, Vince JE (2016) New insights into the regulation of innate immunity by caspase-8. Arthritis Res Ther 18(1):1–3. doi:10.1186/s13075-015-0910-0

    Article  Google Scholar 

  89. Khan N, Lawlor KE, Murphy JM, Vince JE (2014) More to life than death: molecular determinants of necroptotic and non-necroptotic RIP3 kinase signaling. Curr Opin Immunol 26:76–89. doi:10.1016/j.coi.2013.10.017

    Article  CAS  PubMed  Google Scholar 

  90. Man SM, Tourlomousis P, Hopkins L, Monie TP, Fitzgerald KA, Bryant CE (2013) Salmonella infection induces recruitment of caspase-8 to the inflammasome to modulate IL-1beta production. J Immunol 191(10):5239–5246. doi:10.4049/jimmunol.1301581

    Article  CAS  PubMed  Google Scholar 

  91. Gurung P, Anand PK, Malireddi RK, Vande Walle L, Van Opdenbosch N, Dillon CP, Weinlich R, Green DR, Lamkanfi M, Kanneganti TD (2014) FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J Immunol 192(4):1835–1846. doi:10.4049/jimmunol.1302839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bossaller L, Chiang PI, Schmidt-Lauber C, Ganesan S, Kaiser WJ, Rathinam VA, Mocarski ES, Subramanian D, Green DR, Silverman N, Fitzgerald KA, Marshak-Rothstein A, Latz E (2012) Cutting Edge: FAS (CD95) mediates noncanonical IL-1beta and IL-18 maturation via caspase-8 in an RIP3-independent manner. J Immunol 189(12):5508–5512. doi:10.4049/jimmunol.1202121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pierini R, Perret M, Djebali S, Juruj C, Michallet MC, Forster I, Marvel J, Walzer T, Henry T (2013) ASC controls IFN-gamma levels in an IL-18-dependent manner in caspase-1-deficient mice infected with Francisella novicida. J Immunol 191(7):3847–3857. doi:10.4049/jimmunol.1203326

    Article  CAS  PubMed  Google Scholar 

  94. Pierini R, Juruj C, Perret M, Jones CL, Mangeot P, Weiss DS, Henry T (2012) AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages. Cell Death Differ 19(10):1709–1721. doi:10.1038/cdd.2012.51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lukens JR, Gurung P, Vogel P, Johnson GR, Carter RA, McGoldrick DJ, Bandi SR, Calabrese CR, Vande Walle L, Lamkanfi M, Kanneganti TD (2014) Dietary modulation of the microbiome affects autoinflammatory disease. Nature 516(7530):246–249. doi:10.1038/nature13788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vieira AT, Macia L, Galvao I, Martins FS, Canesso MC, Amaral FA, Garcia CC, Maslowski KM, De Leon E, Shim D, Nicoli JR, Harper JL, Teixeira MM, Mackay CR (2015) A role for Gut Microbiota and the Metabolite-Sensing Receptor GPR43 in a Murine Model of Gout. Arthritis Rheumatol (Hoboken, NJ) 67(6):1646–1656. doi:10.1002/art.39107

    Article  CAS  Google Scholar 

  97. Macia L, Tan J, Vieira AT, Leach K, Stanley D, Luong S, Maruya M, Ian McKenzie C, Hijikata A, Wong C, Binge L, Thorburn AN, Chevalier N, Ang C, Marino E, Robert R, Offermanns S, Teixeira MM, Moore RJ, Flavell RA, Fagarasan S, Mackay CR (2015) Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun 6:6734. doi:10.1038/ncomms7734

    Article  CAS  PubMed  Google Scholar 

  98. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482(7384):179–185. doi:10.1038/nature10809

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 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(5):745–757. doi:10.1016/j.cell.2011.04.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Levy M, Thaiss CA, Zeevi D, Dohnalova 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(6):1428–1443. doi:10.1016/j.cell.2015.10.048

    Article  CAS  PubMed  Google Scholar 

  101. Cuda CM, Misharin AV, Khare S, Saber R, Tsai F, Archer AM, Homan PJ, Haines GK 3rd, Hutcheson J, Dorfleutner A, Budinger GR, Stehlik C, Perlman H (2015) Conditional deletion of caspase-8 in macrophages alters macrophage activation in a RIPK-dependent manner. Arthritis Res Ther 17:291. doi:10.1186/s13075-015-0794-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A (2011) Microbiota regulates immune defense against respiratory tract influenza a virus infection. Proc Natl Acad Sci USA 108(13):5354–5359. doi:10.1073/pnas.1019378108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sauter KA, Wood LJ, Wong J, Iordanov M, Magun BE (2011) Doxorubicin and daunorubicin induce processing and release of interleukin-1beta through activation of the NLRP3 inflammasome. Cancer Biol Ther 11(12):1008–1016 (Epub 2011 Jun 1015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, Lich JD, Finger J, Kasparcova V, Votta B, Ouellette M, King BW, Wisnoski D, Lakdawala AS, DeMartino MP, Casillas LN, Haile PA, Sehon CA, Marquis RW, Upton J, Daley-Bauer LP, Roback L, Ramia N, Dovey CM, Carette JE, Chan FK, Bertin J, Gough PJ, Mocarski ES, Kaiser WJ (2014) RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell 56(4):481–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D, Komuves L, Ferrando RE, French DM, Webster J, Roose-Girma M, Warming S, Dixit VM (2014) Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343(6177):1357–1360. doi:10.1126/science.1249361

    Article  CAS  PubMed  Google Scholar 

  106. Kang S, Fernandes-Alnemri T, Rogers C, Mayes L, Wang Y, Dillon C, Roback L, Kaiser W, Oberst A, Sagara J, Fitzgerald KA, Green DR, Zhang J, Mocarski ES, Alnemri ES (2015) Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. Nat Commun 6:7515. doi:10.1038/ncomms8515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M, Zhu L, Katsuyama T, Sagara J, Taniguchi S, Gumucio DL, Nunez G, Inohara N (2003) ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Biochem Biophys Res Commun 303(1):69–73

    Article  CAS  PubMed  Google Scholar 

  108. Masumoto J, Taniguchi S, Ayukawa K, Sarvotham H, Kishino T, Niikawa N, Hidaka E, Katsuyama T, Higuchi T, Sagara J (1999) ASC, a novel 22 kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem 274(48):33835–33838

    Article  CAS  PubMed  Google Scholar 

  109. 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(9):1149–1160. doi:10.1038/cdd.2013.37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Vajjhala PR, Lu A, Brown DL, Pang SW, Sagulenko V, Sester DP, Cridland SO, Hill JM, Schroder K, Stow JL, Wu H, Stacey KJ (2015) The Inflammasome Adaptor ASC Induces Procaspase-8 Death Effector Domain Filaments. J Biol Chem 290(49):29217–29230. doi:10.1074/jbc.M115.687731

    Article  CAS  PubMed  Google Scholar 

  111. Antonopoulos C, Russo HM, El Sanadi C, Martin BN, Li X, Kaiser WJ, Mocarski ES, Dubyak GR (2015) Caspase-8 as an effector and regulator of NLRP3 inflammasome signaling. J Biol Chem 290(33):20167–20184. doi:10.1074/jbc.M115.652321

    Article  CAS  PubMed  Google Scholar 

  112. Schroder K, Sagulenko V, Zamoshnikova A, Richards AA, Cridland JA, Irvine KM, Stacey KJ, Sweet MJ (2012) Acute lipopolysaccharide priming boosts inflammasome activation independently of inflammasome sensor induction. Immunobiology 217(12):1325–1329. doi:10.1016/j.imbio.2012.07.020

    Article  CAS  PubMed  Google Scholar 

  113. Fernandes-Alnemri T, Kang S, Anderson C, Sagara J, Fitzgerald KA, Alnemri ES (2013) Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J Immunol 191(8):3995–3999. doi:10.4049/jimmunol.1301681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ghonime MG, Shamaa OR, Das S, Eldomany RA, Fernandes-Alnemri T, Alnemri ES, Gavrilin MA, Wewers MD (2014) Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol 192(8):3881–3888. doi:10.4049/jimmunol.1301974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES (2012) Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem 287(43):36617–36622. doi:10.1074/jbc.M112.407130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Silke J, Meier P (2013) Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Cold Spring Harb Perspect Biol. doi:10.1101/cshperspect.a008730

    PubMed  PubMed Central  Google Scholar 

  117. Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW, Nachbur U, Gangoda L, Warnken U, Purcell AW, Silke J, Walczak H (2011) Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471(7340):591–596. doi:10.1038/nature09816

    Article  CAS  PubMed  Google Scholar 

  118. Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T, Koschny R, Komander D, Silke J, Walczak H (2009) Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 36(5):831–844. doi:10.1016/j.molcel.2009.10.013

    Article  CAS  PubMed  Google Scholar 

  119. Yang X, Miyawaki T, Kanegane H (2012) SAP and XIAP deficiency in hemophagocytic lymphohistiocytosis. Pediatr Int 54(4):447–454. doi:10.1111/j.1442-1200X.2012.03683.x

    Article  CAS  PubMed  Google Scholar 

  120. Wada T, Kanegane H, Ohta K, Katoh F, Imamura T, Nakazawa Y, Miyashita R, Hara J, Hamamoto K, Yang X, Filipovich AH, Marsh RA, Yachie A (2014) Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency. Cytokine 65(1):74–78. doi:10.1016/j.cyto.2013.1009.1007

    Article  CAS  PubMed  Google Scholar 

  121. Takada H, Ohga S, Mizuno Y, Suminoe A, Matsuzaki A, Ihara K, Kinukawa N, Ohshima K, Kohno K, Kurimoto M, Hara T (1999) Oversecretion of IL-18 in haemophagocytic lymphohistiocytosis: a novel marker of disease activity. Br J Haematol 106(1):182–189

    Article  CAS  PubMed  Google Scholar 

  122. Standing A, Eleftheriou D, Omoyinmi E, Chieng A, Klein N, Lachmann H, Hawkins P, Gilmour K, Brogan P (2012) A novel mutation in the X-linked inhibitor of apoptosis protein causing a multi-system autoinflammatory disorder. Ann Paediatr Rheum 1(4):227–230

    Article  Google Scholar 

  123. Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E, Xu Z, Abhyankar A, Israel L, Trevejo-Nunez G, Bogunovic D, Cepika AM, MacDuff D, Chrabieh M, Hubeau M, Bajolle F, Debre M, Mazzolari E, Vairo D, Agou F, Virgin HW, Bossuyt X, Rambaud C, Facchetti F, Bonnet D, Quartier P, Fournet JC, Pascual V, Chaussabel D, Notarangelo LD, Puel A, Israel A, Casanova JL, Picard C (2012) Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 13(12):1178–1186. doi:10.1038/ni.2457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Boisson B, Laplantine E, Dobbs K, Cobat A, Tarantino N, Hazen M, Lidov HG, Hopkins G, Du L, Belkadi A, Chrabieh M, Itan Y, Picard C, Fournet JC, Eibel H, Tsitsikov E, Pai SY, Abel L, Al-Herz W, Casanova JL, Israel A, Notarangelo LD (2015) Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med 212(6):939–951. doi:10.1084/jem.20141130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Rickard JA, Anderton H, Etemadi N, Nachbur U, Darding M, Peltzer N, Lalaoui N, Lawlor KE, Vanyai H, Hall C, Bankovacki A, Gangoda L, Wong WW, Corbin J, Huang C, Mocarski ES, Murphy JM, Alexander WS, Voss AK, Vaux DL, Kaiser WJ, Walczak H, Silke J (2014) TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. eLife. doi:10.7554/eLife.03464

    PubMed  Google Scholar 

  126. Kumari S, Redouane Y, Lopez-Mosqueda J, Shiraishi R, Romanowska M, Lutzmayer S, Kuiper J, Martinez C, Dikic I, Pasparakis M, Ikeda F (2014) Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. eLife. doi:10.7554/eLife.03422

    PubMed  Google Scholar 

  127. Liang Y, Seymour RE, Sundberg JP (2011) Inhibition of NF-kappaB signaling retards eosinophilic dermatitis in SHARPIN-deficient mice. J Invest Dermatol 131(1):141–149. doi:10.1038/jid.2010.259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ikeda F, Deribe YL, Skanland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJ, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I (2011) SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature 471(7340):637–641. doi:10.1038/nature09814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, Capriotti C, Cook M, Finger J, Hughes-Earle A, Harris PA, Kaiser WJ, Mocarski ES, Bertin J, Gough PJ (2014) Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J Immunol 192(12):5476–5480. doi:10.4049/jimmunol.1400499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Douglas T, Champagne C, Morizot A, Lapointe JM, Saleh M (2015) The inflammatory caspases-1 and -11 mediate the pathogenesis of dermatitis in sharpin-deficient mice. J Immunol 195(5):2365–2373. doi:10.4049/jimmunol.1500542

    Article  CAS  PubMed  Google Scholar 

  131. Tokunaga F (2013) Linear ubiquitination-mediated NF-kappaB regulation and its related disorders. J Biochem 154(4):313–323. doi:10.1093/jb/mvt079

    Article  CAS  PubMed  Google Scholar 

  132. Gurung P, Lamkanfi M, Kanneganti TD (2015) Cutting edge: SHARPIN is required for optimal NLRP3 inflammasome activation. J Immunol 194(5):2064–2067. doi:10.4049/jimmunol.1402951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zak DE, Schmitz F, Gold ES, Diercks AH, Peschon JJ, Valvo JS, Niemisto A, Podolsky I, Fallen SG, Suen R, Stolyar T, Johnson CD, Kennedy KA, Hamilton MK, Siggs OM, Beutler B, Aderem A (2011) Systems analysis identifies an essential role for SHANK-associated RH domain-interacting protein (SHARPIN) in macrophage Toll-like receptor 2 (TLR2) responses. Proc Natl Acad Sci USA 108(28):11536–11541. doi:10.1073/pnas.1107577108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rodgers MA, Bowman JW, Fujita H, Orazio N, Shi M, Liang Q, Amatya R, Kelly TJ, Iwai K, Ting J, Jung JU (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211(7):1333–1347. doi:10.1084/jem.20132486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T, Tavares R, Prodhomme T, Duong B, Whang MI, Advincula R, Agelidis A, Barrera J, Wu H, Burlingame A, Malynn BA, Zamvil SS, Ma A (2015) The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 16(6):618–627. doi:10.1038/ni.3172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Vande Walle L, Van Opdenbosch N, Jacques P, Fossoul A, Verheugen E, Vogel P, Beyaert R, Elewaut D, Kanneganti TD, van Loo G, Lamkanfi M (2014) Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature 512(7512):69–73. doi:10.1038/nature13322

    PubMed  Google Scholar 

  137. Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, Yu Z, Mullikin JC, Hasni SA, Wertz IE, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, van Royen-Kerkof A, Sibley C, Batu ED, Gul A, Siegel RM, Boehm M, Milner JD, Ozen S, Gadina M, Chae J, Laxer RM, Kastner DL, Aksentijevich I (2016) Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early onset autoinflammatory disease. Nat Genet 48(1):67–73. doi:10.1038/ng.3459

    Article  CAS  PubMed  Google Scholar 

  138. White MJ, McArthur K, Metcalf D, Lane RM, Cambier JC, Herold MJ, van Delft MF, Bedoui S, Lessene G, Ritchie ME, Huang DC, Kile BT (2014) Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159(7):1549–1562. doi:10.1016/j.cell.2014.11.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Rongvaux A, Jackson R, Harman CC, Li T, West AP, de Zoete MR, Wu Y, Yordy B, Lakhani SA, Kuan CY, Taniguchi T, Shadel GS, Chen ZJ, Iwasaki A, Flavell RA (2014) Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159(7):1563–1577. doi:10.1016/j.cell.2014.11.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Martin SJ, Henry CM, Cullen SP (2012) A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol Cell 46(4):387–397. doi:10.1016/j.molcel.2012.04.026

    Article  CAS  PubMed  Google Scholar 

  141. Etemadi N, Chopin M, Anderton H, Tanzer MC, Rickard JA, Abeysekra W, Hall C, Spall SK, Wang B, Xiong Y, Hla T, Hla T, Pitson SM, Bonder CS, Wong WW, Ernst M, Smyth GK, Vaux DL, Nutt SL, Nachbur U, Silke J (2015) TRAF2 regulates TNF and NF-kappaB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase-1. eLife. doi:10.7554/eLife.10592

    PubMed  Google Scholar 

  142. Panayotova-Dimitrova D, Feoktistova M, Ploesser M, Kellert B, Hupe M, Horn S, Makarov R, Jensen F, Porubsky S, Schmieder A, Zenclussen AC, Marx A, Kerstan A, Geserick P, He YW, Leverkus M (2013) cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep 5(2):397–408. doi:10.1016/j.celrep.2013.09.035

    Article  CAS  PubMed  Google Scholar 

  143. Guan K, Wei C, Zheng Z, Song T, Wu F, Zhang Y, Cao Y, Ma S, Chen W, Xu Q, Xia W, Gu J, He X, Zhong H (2015) MAVS promotes inflammasome activation by targeting ASC for K63-linked ubiquitination via the E3 ligase TRAF3. J Immunol 194(10):4880–4890. doi:10.4049/jimmunol.1402851

    Article  CAS  PubMed  Google Scholar 

  144. Franchi L, Eigenbrod T, Muñoz-Planillo R, Ozkurede U, Kim YG, Chakrabarti A, Gale M Jr, Silverman RH, Colonna M, Akira S, Núñez G (2014) Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K + efflux. J Immunol 193(8):4214–4222. doi:10.4049/jimmunol.1400582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN (2013) The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153(2):348–361. doi:10.1016/j.cell.2013.02.054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ichinohe T, Yamazaki T, Koshiba T, Yanagi Y (2013) Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection. Proc Natl Acad Sci USA 110(44):17963–17968. doi:10.1073/pnas.1312571110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Moriwaki K, Farias Luz N, Balaji S, De Rosa MJ, O’Donnell CL, Gough PJ, Bertin J, Welsh RM, Chan FK (2016) The mitochondrial phosphatase PGAM5 is dispensable for necroptosis but promotes inflammasome activation in macrophages. J Immunol 196(1):407–415. doi:10.4049/jimmunol.1501662

    Article  CAS  PubMed  Google Scholar 

  148. Yu J, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, Horng T (2014) Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci USA 111(43):15514–15519. doi:10.1073/pnas.1414859111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Murphy JM, Vince JE (2015) Post-translational control of RIPK3 and MLKL mediated necroptotic cell death. doi:10.12688/f1000research.7046.1 (F1000Research 4 (1297))

  150. Murphy JM, Silke J (2014) Ars Moriendi; the art of dying well—new insights into the molecular pathways of necroptotic cell death. EMBO Rep 15(2):155–164. doi:10.1002/embr.201337970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kitur K, Parker D, Nieto P, Ahn DS, Cohen TS, Chung S, Wachtel S, Bueno S, Prince A (2015) Toxin-induced necroptosis is a major mechanism of Staphylococcus aureus lung damage. PLoS Pathog 11(4):e1004820. doi:10.1371/journal.ppat.1004820

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, Ye J, Zhang X, Chang A, Vakifahmetoglu-Norberg H, Geng J, Py B, Zhou W, Amin P, Berlink Lima J, Qi C, Yu Q, Trapp B, Yuan J (2015) Activation of necroptosis in multiple sclerosis. Cell Rep 10(11):1836–1849. doi:10.1016/j.celrep.2015.02.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lin J, Li H, Yang M, Ren J, Huang Z, Han F, Huang J, Ma J, Zhang D, Zhang Z, Wu J, Huang D, Qiao M, Jin G, Wu Q, Huang Y, Du J, Han J (2013) A role of RIP3-mediated macrophage necrosis in atherosclerosis development. Cell Rep 3(1):200–210. doi:10.1016/j.celrep.2012.12.012

    Article  CAS  PubMed  Google Scholar 

  154. Inoue M, Shinohara ML (2013) The role of interferon-beta in the treatment of multiple sclerosis and experimental autoimmune encephalomyelitis—in the perspective of inflammasomes. Immunology 139(1):11–18. doi:10.1111/imm.12081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Sheedy FJ, Moore KJ (2013) IL-1 signaling in atherosclerosis: sibling rivalry. Nat Immunol 14(10):1030–1032. doi:10.1038/ni.2711

    Article  CAS  PubMed  Google Scholar 

  156. Wang X, Jiang W, Yan Y, Gong T, Han J, Tian Z, Zhou R (2014) RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway. Nat Immunol 15(12):1126–1133. doi:10.1038/ni.3015

    Article  CAS  PubMed  Google Scholar 

  157. Menu P, Mayor A, Zhou R, Tardivel A, Ichijo H, Mori K, Tschopp J (2012) ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis. doi:10.1038/cddis.2011.1132

    PubMed  PubMed Central  Google Scholar 

  158. Cassel SL, Janczy JR, Bing X, Wilson SP, Olivier AK, Otero JE, Iwakura Y, Shayakhmetov DM, Bassuk AG, Abu-Amer Y, Brogden KA, Burns TL, Sutterwala FS, Ferguson PJ (2014) Inflammasome-independent IL-1beta mediates autoinflammatory disease in Pstpip2-deficient mice. Proc Natl Acad Sci USA 111(3):1072–1077. doi:10.1073/pnas.1318685111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Lukens JR, Gross JM, Calabrese C, Iwakura Y, Lamkanfi M, Vogel P, Kanneganti TD (2014) Critical role for inflammasome-independent IL-1beta production in osteomyelitis. Proc Natl Acad Sci USA 111(3):1066–1071. doi:10.1073/pnas.1318688111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Philip NH, Dillon CP, Snyder AG, Fitzgerald P, Wynosky-Dolfi MA, Zwack EE, Hu B, Fitzgerald L, Mauldin EA, Copenhaver AM, Shin S, Wei L, Parker M, Zhang J, Oberst A, Green DR, Brodsky IE (2014) Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-kappaB and MAPK signaling. Proc Natl Acad Sci USA. doi:10.1073/pnas.1403252111

    PubMed  PubMed Central  Google Scholar 

  161. Weng D, Marty-Roix R, Ganesan S, Proulx MK, Vladimer GI, Kaiser WJ, Mocarski ES, Pouliot K, Chan FK, Kelliher MA, Harris PA, Bertin J, Gough PJ, Shayakhmetov DM, Goguen JD, Fitzgerald KA, Silverman N, Lien E (2014) Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death. Proc Natl Acad Sci USA 111(20):7391–7396. doi:10.1073/pnas.1403477111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 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-1beta production in acute glaucoma. Proc Natl Acad Sci USA 111(30):11181–11186. doi:10.1073/pnas.1402819111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Rickard JA, O’Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers TW, Vince JE, Lawlor KE, Ninnis RL, Anderton H, Hall C, Spall SK, Phesse TJ, Abud HE, Cengia LH, Corbin J, Mifsud S, Di Rago L, Metcalf D, Ernst M, Dewson G, Roberts AW, Alexander WS, Murphy JM, Ekert PG, Masters SL, Vaux DL, Croker BA, Gerlic M, Silke J (2014) RIPK1 regulates RIPK3-MLKL driven systemic inflammation and emergency hematopoiesis. Cell 157(2):1175–1188

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors’ work is supported by National Health and Medical Research (Canberra, Australia) Project grants (JEV: 1051210, 1101405), fellowships (JEV: 1052598 and JS: 541901, 1058190) and operational infrastructure grants through the Australian Government IRISS and the Victorian State Government OIS.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to James E. Vince.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vince, J.E., Silke, J. The intersection of cell death and inflammasome activation. Cell. Mol. Life Sci. 73, 2349–2367 (2016). https://doi.org/10.1007/s00018-016-2205-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-016-2205-2

Keywords

Navigation