Inflammasomes are key inflammatory signaling platforms that detect microbial substances, sterile environmental insults, and molecules derived from host cells. Activation of the inflammasome promotes caspase-1-mediated secretion of proinflammatory cytokines interleukin (IL)-1β and IL-18 and pyroptosis. Recent developments in this field demonstrate the crucial role of the inflammasome in a wide range of disease models. Although inflammasomes are a crucial part of host defense mechanisms against pathogens, the exuberant immune response resulting from inflammasome activation also contributes to the development of various diseases. As ongoing studies further elucidate the regulation and function of the inflammasome, more evidence has emerged that the inflammasome appears to play a pivotal role in the development of multiple inflammatory diseases. Here, we discuss recent insights into how inflammasomes are regulated to activate caspase-1 and implicated in human diseases. We also review the contributions of the inflammasome to pulmonary diseases.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Chen GY, Nuñez G. 1.  2010. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10:826–37 [Google Scholar]
  2. Krysko DV, Agostinis P, Krysko O, Garg AD, Bachert C. 2.  et al. 2011. Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol 32:157–64 [Google Scholar]
  3. Takeuchi O, Akira S. 3.  2010. Pattern recognition receptors and inflammation. Cell 140:805–20 [Google Scholar]
  4. Martinon F, Mayor A, Tschopp J. 4.  2009. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27:229–65 [Google Scholar]
  5. Davis BK, Wen H, Ting JP. 5.  2011. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol. 29:707–35 [Google Scholar]
  6. Dinarello CA. 6.  2009. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27:519–50 [Google Scholar]
  7. Dinarello CA. 7.  2006. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am. J. Clin. Nutr. 83:447S–55S [Google Scholar]
  8. Trøseid M, Seljeflot I, Arnesen H. 8.  2010. The role of interleukin-18 in the metabolic syndrome. Cardiovasc. Diabetol. 9:11 [Google Scholar]
  9. Bergsbaken T, Fink SL, Cookson BT. 9.  2009. Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol. 7:99–109 [Google Scholar]
  10. Lamkanfi M, Dixit VM. 10.  2014. Mechanisms and functions of inflammasomes. Cell 157:1013–22 [Google Scholar]
  11. von Moltke J, Trinidad NJ, Moayeri M, Kintzer AF, Wang SB. 11.  et al. 2012. Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490:107–11 [Google Scholar]
  12. Menzel DB AM. 12.  1986. Toxic response of the respiratory system. Casarett and Doull's Toxicology: The Basic Science of Poisons K Klaassen, MO Amdur, J Doull 330–58 New York: MacMillan, 3rd ed.. [Google Scholar]
  13. Martinon F, Burns K, Tschopp J. 13.  2002. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β.. Mol. Cell 10:417–26 [Google Scholar]
  14. Guey B, Bodnar M, Manié SN, Tardivel A, Petrilli V. 14.  2014. Caspase-1 autoproteolysis is differentially required for NLRP1b and NLRP3 inflammasome function. PNAS 111:17254–59 [Google Scholar]
  15. Thoren KL, Krantz BA. 15.  2011. The unfolding story of anthrax toxin translocation. Mol. Microbiol. 80:588–95 [Google Scholar]
  16. Turk BE. 16.  2007. Manipulation of host signalling pathways by anthrax toxins. Biochem. J. 402:405–17 [Google Scholar]
  17. Boyden ED, Dietrich WF. 17.  2006. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat. Genet 38:240–44 [Google Scholar]
  18. Van Opdenbosch N, Gurung P, Vande Walle L, Fossoul A, Kanneganti TD, Lamkanfi M. 18.  2014. Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation. Nat. Commun. 5:320 [Google Scholar]
  19. Terra JK, Cote CK, France B, Jenkins AL, Bozue JA. 19.  et al. 2010. Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b. . J. Immunol. 184:17–20 [Google Scholar]
  20. Moayeri M, Crown D, Newman ZL, Okugawa S, Eckhaus M. 20.  et al. 2010. Inflammasome sensor Nlrp1b-dependent resistance to anthrax is mediated by caspase-1, IL-1 signaling and neutrophil recruitment. PLOS Pathog 6:e1001222 [Google Scholar]
  21. Muehlbauer SM, Evering TH, Bonuccelli G, Squires RC, Ashton AW. 21.  et al. 2007. Anthrax lethal toxin kills macrophages in a strain-specific manner by apoptosis or caspase-1-mediated necrosis. Cell Cycle 6:758–66 [Google Scholar]
  22. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A. 22.  et al. 2003. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 278:8869–72 [Google Scholar]
  23. Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S. 23.  et al. 2008. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1β secretion in response to Bacillus anthracis infection and muramyl dipeptide. PNAS 105:7803–8 [Google Scholar]
  24. Ferwerda G, Kramer M, de Jong D, Piccini A, Joosten LA. 24.  et al. 2008. Engagement of NOD2 has a dual effect on proIL-1β mRNA transcription and secretion of bioactive IL-1β.. Eur. J. Immunol. 38:184–91 [Google Scholar]
  25. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K. 25.  et al. 2009. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183:787–91 [Google Scholar]
  26. Moon JS, Lee S, Park MA, Siempos II, Haslip M. 26.  et al. 2015. UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J. Clin. Investig. 125:665–80 [Google Scholar]
  27. Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. 27.  2012. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J. Biol. Chem. 287:36617–22 [Google Scholar]
  28. Schroder K, Sagulenko V, Zamoshnikova A, Richards AA, Cridland JA. 28.  et al. 2012. Acute lipopolysaccharide priming boosts inflammasome activation independently of inflammasome sensor induction. Immunobiology 217:1325–29 [Google Scholar]
  29. Py BF, Kim MS, Vakifahmetoglu-Norberg H, Yuan J. 29.  2013. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol. Cell 49:331–38 [Google Scholar]
  30. Fernandes-Alnemri T, Kang S, Anderson C, Sagara J, Fitzgerald KA, Alnemri ES. 30.  2013. Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J. Immunol. 191:3995–99 [Google Scholar]
  31. von Moltke J, Ayres JS, Kofoed EM, Chavarria-Smith J, Vance RE. 31.  2013. Recognition of bacteria by inflammasomes. Annu. Rev. Immunol. 31:73–106 [Google Scholar]
  32. Muñoz-Planillo R, Kuffa P, Martínez-Colón G, Smith BL, Rajendiran TM, Nuñez G. 32.  2013. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38:1142–53 [Google Scholar]
  33. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T. 33.  et al. 2011. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12:222–30 [Google Scholar]
  34. Zhou R, Yazdi AS, Menu P, Tschopp J. 34.  2011. A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–25 [Google Scholar]
  35. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N. 35.  et al. 2012. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401–14 [Google Scholar]
  36. Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S. 36.  et al. 2016. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164:896–910 [Google Scholar]
  37. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG. 37.  et al. 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-β.. Nat. Immunol. 9:857–65 [Google Scholar]
  38. Zhang Q, Kuang H, Chen C, Yan J, Do-Umehara HC. 38.  et al. 2015. The kinase Jnk2 promotes stress-induced mitophagy by targeting the small mitochondrial form of the tumor suppressor ARF for degradation. Nat. Immunol. 16:458–66 [Google Scholar]
  39. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M. 39.  et al. 2012. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13:255–63 [Google Scholar]
  40. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H. 40.  et al. 2008. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9:847–56 [Google Scholar]
  41. Choi AM, Ryter SW, Levine B. 41.  2013. Autophagy in human health and disease. N. Engl. J. Med. 368:1845–46 [Google Scholar]
  42. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG. 42.  et al. 2008. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456:264–68 [Google Scholar]
  43. Harris J, Hartman M, Roche C, Zeng SG, O'Shea A. 43.  et al. 2011. Autophagy controls IL-1β secretion by targeting pro-IL-1β for degradation. J. Biol. Chem. 286:9587–97 [Google Scholar]
  44. Youle RJ, Narendra DP. 44.  2011. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12:9–14 [Google Scholar]
  45. Broz P, von Moltke J, Jones JW, Vance RE, Monack DM. 45.  2010. Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing. Cell Host Microbe 8:471–83 [Google Scholar]
  46. Mariathasan S, Newton K, Monack DM, Vucic D, French DM. 46.  et al. 2004. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–18 [Google Scholar]
  47. Qu Y, Misaghi S, Izrael-Tomasevic A, Newton K, Gilmour LL. 47.  et al. 2012. Phosphorylation of NLRC4 is critical for inflammasome activation. Nature 490:539–42 [Google Scholar]
  48. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. 48.  2009. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458:509–13 [Google Scholar]
  49. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G. 49.  et al. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458:514–18 [Google Scholar]
  50. Jin T, Perry A, Jiang J, Smith P, Curry JA. 50.  et al. 2012. Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36:561–71 [Google Scholar]
  51. Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S. 51.  et al. 2010. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat. Immunol. 11:385–93 [Google Scholar]
  52. Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE. 52.  et al. 2010. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11:395–402 [Google Scholar]
  53. Sauer JD, Witte CE, Zemansky J, Hanson B, Lauer P, Portnoy DA. 53.  2010. Listeria monocytogenes triggers AIM2-mediated pyroptosis upon infrequent bacteriolysis in the macrophage cytosol. Cell Host Microbe 7:412–19 [Google Scholar]
  54. Wu J, Fernandes-Alnemri T, Alnemri ES. 54.  2010. Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. J. Clin. Immunol. 30:693–702 [Google Scholar]
  55. Yu C, Gershwin ME, Chang C. 55.  2014. Diagnostic criteria for systemic lupus erythematosus: a critical review. J. Autoimmun. 48–49:10–13 [Google Scholar]
  56. Zhang W, Cai Y, Xu W, Yin Z, Gao X, Xiong S. 56.  2013. AIM2 facilitates the apoptotic DNA-induced systemic lupus erythematosus via arbitrating macrophage functional maturation. J. Clin. Immunol. 33:925–37 [Google Scholar]
  57. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S. 57.  et al. 2011. Non-canonical inflammasome activation targets caspase-11. Nature 479:117–21 [Google Scholar]
  58. Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC. 58.  et al. 2013. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341:1246–49 [Google Scholar]
  59. Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C. 59.  et al. 2012. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150:606–19 [Google Scholar]
  60. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA. 60.  2013. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341:1250–53 [Google Scholar]
  61. Kajiwara Y, Schiff T, Voloudakis G, Gama Sosa MA, Elder G. 61.  et al. 2014. A critical role for human caspase-4 in endotoxin sensitivity. J. Immunol. 193:335–43 [Google Scholar]
  62. Huang MT, Taxman DJ, Holley-Guthrie EA, Moore CB, Willingham SB. 62.  et al. 2009. Critical role of apoptotic speck protein containing a caspase recruitment domain (ASC) and NLRP3 in causing necrosis and ASC speck formation induced by Porphyromonas gingivalis in human cells. J. Immunol. 182:2395–404 [Google Scholar]
  63. Bryan NB, Dorfleutner A, Rojanasakul Y, Stehlik C. 63.  2009. Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain. J. Immunol. 182:3173–82 [Google Scholar]
  64. Cai X, Chen J, Xu H, Liu S, Jiang QX. 64.  et al. 2014. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156:1207–22 [Google Scholar]
  65. Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E. 65.  et al. 2013. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat. Immunol. 14:1247–55 [Google Scholar]
  66. Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A. 66.  et al. 2014. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat. Immunol. 15:727–37 [Google Scholar]
  67. O'Neill LA, Pearce EJ. 67.  2016. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213:15–23 [Google Scholar]
  68. Fleury C, Neverova M, Collins S, Raimbault S, Champigny O. 68.  et al. 1997. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat. Genet. 15:269–72 [Google Scholar]
  69. Rousset S, Alves-Guerra MC, Mozo J, Miroux B, Cassard-Doulcier AM. 69.  et al. 2004. The biology of mitochondrial uncoupling proteins. Diabetes 53:Suppl. 1S130–35 [Google Scholar]
  70. Zhang J, Khvorostov I, Hong JS, Oktay Y, Vergnes L. 70.  et al. 2011. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J 30:4860–73 [Google Scholar]
  71. Moon JS, Nakahira K, Chung KP, DeNicola GM, Koo MJ. 71.  et al. 2016. NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat. Med. 22:1002–12 [Google Scholar]
  72. Kelly B, O'Neill LA. 72.  2015. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 25:771–84 [Google Scholar]
  73. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. 73.  2010. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11:136–40 [Google Scholar]
  74. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF. 74.  et al. 2013. Succinate is an inflammatory signal that induces IL-1β through HIF-1α.. Nature 496:238–42 [Google Scholar]
  75. Moon JS, Hisata S, Park MA, DeNicola GM, Ryter SW. 75.  et al. 2015. mTORC1-induced HK1-dependent glycolysis regulates NLRP3 inflammasome activation. Cell Rep 12:102–15 [Google Scholar]
  76. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI. 76.  et al. 2010. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39:171–83 [Google Scholar]
  77. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH. 77.  et al. 2004. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–99 [Google Scholar]
  78. Wen H, Gris D, Lei Y, Jha S, Zhang L. 78.  et al. 2011. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12:408–15 [Google Scholar]
  79. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G. 79.  et al. 2010. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–61 [Google Scholar]
  80. Chu J, Thomas LM, Watkins SC, Franchi L, Nuñez G, Salter RD. 80.  2009. Cholesterol-dependent cytolysins induce rapid release of mature IL-1β from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner. J. Leukoc. Biol. 86:1227–38 [Google Scholar]
  81. Guo H, Callaway JB, Ting JP. 81.  2015. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21:677–87 [Google Scholar]
  82. Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA. 82.  et al. 2007. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356:1517–26 [Google Scholar]
  83. Cavelti-Weder C, Furrer R, Keller C, Babians-Brunner A, Solinger AM. 83.  et al. 2011. Inhibition of IL-1β improves fatigue in type 2 diabetes. Diabetes Care 34:e158 [Google Scholar]
  84. Donath MY. 84.  2014. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat. Rev. Drug Discov. 13:465–76 [Google Scholar]
  85. Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A. 85.  et al. 2009. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J. Cell Biol. 187:61–70 [Google Scholar]
  86. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K. 86.  et al. 2011. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17:179–88 [Google Scholar]
  87. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM. 87.  et al. 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 [Google Scholar]
  88. Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G. 88.  et al. 2013. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat. Med. 19:1132–40 [Google Scholar]
  89. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S. 89.  et al. 2013. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493:674–78 [Google Scholar]
  90. Broderick L, De Nardo D, Franklin BS, Hoffman HM, Latz E. 90.  2015. The inflammasomes and autoinflammatory syndromes. Annu. Rev. Pathol. 10:395–424 [Google Scholar]
  91. Conforti-Andreoni C, Ricciardi-Castagnoli P, Mortellaro A. 91.  2011. The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond. Cell Mol. Immunol. 8:135–45 [Google Scholar]
  92. Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E. 92.  et al. 2014. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat. Genet. 46:1135–39 [Google Scholar]
  93. Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B. 93.  et al. 2014. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat. Genet. 46:1140–46 [Google Scholar]
  94. Glorioso N, Herrera VL, Didishvili T, Ortu MF, Zaninello R. 94.  et al. 2013. Sex-specific effects of NLRP6/AVR and ADM loci on susceptibility to essential hypertension in a Sardinian population. PLOS ONE 8:e77562 [Google Scholar]
  95. Normand S, Delanoye-Crespin A, Bressenot A, Huot L, Grandjean T. 95.  et al. 2011. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. PNAS 108:9601–6 [Google Scholar]
  96. Kaparakis M, Turnbull L, Carneiro L, Firth S, Coleman HA. 96.  et al. 2010. Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell Microbiol 12:372–85 [Google Scholar]
  97. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M. 97.  et al. 2010. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat. Immunol. 11:1136–42 [Google Scholar]
  98. Leissinger M, Kulkarni R, Zemans RL, Downey GP, Jeyaseelan S. 98.  2014. Investigating the role of nucleotide-binding oligomerization domain-like receptors in bacterial lung infection. Am. J. Respir. Crit. Care Med. 189:1461–68 [Google Scholar]
  99. Willingham SB, Bergstralh DT, O'Connor W, Morrison AC, Taxman DJ. 99.  et al. 2007. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe 2:147–59 [Google Scholar]
  100. Crouch Brewer S, Wunderink RG, Jones CB, Leeper KV Jr. 100.  1996. Ventilator-associated pneumonia due to Pseudomonas aeruginosa. Chest 109:1019–29 [Google Scholar]
  101. Burns JL, Emerson J, Stapp JR, Yim DL, Krzewinski J. 101.  et al. 1998. Microbiology of sputum from patients at cystic fibrosis centers in the United States. Clin. Infect. Dis. 27:158–63 [Google Scholar]
  102. Burns JL, Gibson RL, McNamara S, Yim D, Emerson J. 102.  et al. 2001. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J. Infect. Dis. 183:444–52 [Google Scholar]
  103. Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. 103.  2007. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J. Exp. Med. 204:3235–45 [Google Scholar]
  104. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW. 104.  et al. 2006. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nat. Immunol. 7:569–75 [Google Scholar]
  105. Zhao Y, Yang J, Shi J, Gong YN, Lu Q. 105.  et al. 2011. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477:596–600 [Google Scholar]
  106. Pelegrin P, Surprenant A. 106.  2007. Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1β release through a dye uptake-independent pathway. J. Biol. Chem. 282:2386–94 [Google Scholar]
  107. Kanneganti TD, Lamkanfi M, Kim YG, Chen G, Park JH. 107.  et al. 2007. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26:433–43 [Google Scholar]
  108. Pirhonen J, Sareneva T, Kurimoto M, Julkunen I, Matikainen S. 108.  1999. Virus infection activates IL-1β and IL-18 production in human macrophages by a caspase-1-dependent pathway. J. Immunol. 162:7322–29 [Google Scholar]
  109. Pirhonen J, Sareneva T, Julkunen I, Matikainen S. 109.  2001. Virus infection induces proteolytic processing of IL-18 in human macrophages via caspase-1 and caspase-3 activation. Eur. J. Immunol. 31:726–33 [Google Scholar]
  110. Allen IC, Scull MA, Moore CB, Holl EK, McElvania-TeKippe E. 110.  et al. 2009. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 30:556–65 [Google Scholar]
  111. Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A. 111.  2009. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J. Exp. Med. 206:79–87 [Google Scholar]
  112. Thomas PG, Dash P, Aldridge JR Jr., Ellebedy AH, Reynolds C. 112.  et al. 2009. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30:566–75 [Google Scholar]
  113. Lupfer C, Thomas PG, Anand PK, Vogel P, Milasta S. 113.  et al. 2013. Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat. Immunol. 14:480–88 [Google Scholar]
  114. DeDiego ML, Nieto-Torres JL, Jimenez-Guardeño JM, Regla-Nava JA, Castaño-Rodriguez C. 114.  et al. 2014. Coronavirus virulence genes with main focus on SARS-CoV envelope gene. Virus Res 194:124–37 [Google Scholar]
  115. Ichinohe T, Pang IK, Iwasaki A. 115.  2010. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat. Immunol. 11:404–10 [Google Scholar]
  116. Ito M, Yanagi Y, Ichinohe T. 116.  2012. Encephalomyocarditis virus viroporin 2B activates NLRP3 inflammasome. PLOS Pathog 8:e1002857 [Google Scholar]
  117. McAuley JL, Tate MD, MacKenzie-Kludas CJ, Pinar A, Zeng W. 117.  et al. 2013. Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease. PLOS Pathog 9:e1003392 [Google Scholar]
  118. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. 118.  2012. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev. 76:16–32 [Google Scholar]
  119. Wang CH, Liu CY, Wan YL, Chou CL, Huang KH. 119.  et al. 2005. Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS. Respir. Res. 6:42 [Google Scholar]
  120. Meduri GU, Headley S, Kohler G, Stentz F, Tolley E. 120.  et al. 1995. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1β and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 107:1062–73 [Google Scholar]
  121. Pugin J, Ricou B, Steinberg KP, Suter PM, Martin TR. 121.  1996. Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1. Am. J. Respir. Crit. Care Med. 153:1850–56 [Google Scholar]
  122. Dolinay T, Kim YS, Howrylak J, Hunninghake GM, An CH. 122.  et al. 2012. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am. J. Respir. Crit. Care Med. 185:1225–34 [Google Scholar]
  123. Kuipers MT, Aslami H, Janczy JR, van der Sluijs KF, Vlaar AP. 123.  et al. 2012. Ventilator-induced lung injury is mediated by the NLRP3 inflammasome. Anesthesiology 116:1104–15 [Google Scholar]
  124. Zhang Y, Liu G, Dull RO, Schwartz DE, Hu G. 124.  2014. Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation. Am. J. Physiol. Lung. Cell Mol. Physiol. 307:L173–85 [Google Scholar]
  125. Wu J, Yan Z, Schwartz DE, Yu J, Malik AB, Hu G. 125.  2013. Activation of NLRP3 inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury. J. Immunol. 190:3590–99 [Google Scholar]
  126. Grailer JJ, Canning BA, Kalbitz M, Haggadone MD, Dhond RM. 126.  et al. 2014. Critical role for the NLRP3 inflammasome during acute lung injury. J. Immunol. 192:5974–83 [Google Scholar]
  127. 127. Glob. Initiat. Chronic Obstr. Lung Dis. (GOLD). 2013. Global Strategy for the Diagnosis, Management and Prevention of COPD http://www.goldcopd.org/ [Google Scholar]
  128. Mortaz E, Henricks PA, Kraneveld AD, Givi ME, Garssen J, Folkerts G. 128.  2011. Cigarette smoke induces the release of CXCL-8 from human bronchial epithelial cells via TLRs and induction of the inflammasome. Biochim. Biophys. Acta 1812:1104–10 [Google Scholar]
  129. Lucattelli M, Cicko S, Müller T, Lommatzsch M, De Cunto G. 129.  et al. 2011. P2X7 receptor signaling in the pathogenesis of smoke-induced lung inflammation and emphysema. Am. J. Respir. Cell Mol. Biol. 44:423–29 [Google Scholar]
  130. Eltom S, Belvisi MG, Stevenson CS, Maher SA, Dubuis E. 130.  et al. 2014. Role of the inflammasome-caspase1/11-IL-1/18 axis in cigarette smoke driven airway inflammation: an insight into the pathogenesis of COPD. PLOS ONE 9:e112829 [Google Scholar]
  131. Pauwels NS, Bracke KR, Dupont LL, Van Pottelberge GR, Provoost S. 131.  et al. 2011. Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur. Respir. J. 38:1019–28 [Google Scholar]
  132. Tuder RM, Petrache I. 132.  2012. Pathogenesis of chronic obstructive pulmonary disease. J. Clin. Investig. 122:2749–55 [Google Scholar]
  133. Yang W, Ni H, Wang H, Gu H. 133.  2015. NLRP3 inflammasome is essential for the development of chronic obstructive pulmonary disease. Int. J. Clin. Exp. Pathol. 8:13209–16 [Google Scholar]
  134. Pouwels SD, Zijlstra GJ, van der Toorn M, Hesse L, Gras R. 134.  et al. 2016. Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice. Am. J. Physiol. Lung. Cell Mol. Physiol. 310:L377–86 [Google Scholar]
  135. Kong H, Wang Y, Zeng X, Wang Z, Wang H, Xie W. 135.  2015. Differential expression of inflammasomes in lung cancer cell lines and tissues. Tumor Biol 36:7501–13 [Google Scholar]
  136. Morris GF, Danchuk S, Wang Y, Xu B, Rando RJ. 136.  et al. 2015. Cigarette smoke represses the innate immune response to asbestos. Physiol. Rep. 3:e12652 [Google Scholar]
  137. Wang Y, Kong H, Zeng X, Liu W, Wang Z. 137.  et al. 2016. Activation of NLRP3 inflammasome enhances the proliferation and migration of A549 lung cancer cells. Oncol. Rep. 35:2053–64 [Google Scholar]
  138. Chow MT, Sceneay J, Paget C, Wong CS, Duret H. 138.  et al. 2012. NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases. Cancer Res 72:5721–32 [Google Scholar]
  139. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR. 139.  et al. 2008. The Nalp3 inflammasome is essential for the development of silicosis. PNAS 105:9035–40 [Google Scholar]
  140. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. 140.  2008. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674–77 [Google Scholar]
  141. Gasse P, Riteau N, Charron S, Girre S, Fick L. 141.  et al. 2009. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am. J. Respir. Crit. Care Med. 179:903–13 [Google Scholar]
  142. Gasse P, Mary C, Guenon I, Noulin N, Charron S. 142.  et al. 2007. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J. Clin. Investig. 117:3786–99 [Google Scholar]
  143. Wang R, Ibarra-Sunga O, Verlinski L, Pick R, Uhal BD. 143.  2000. Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. Am. J. Physiol. Lung. Cell Mol. Physiol. 279:L143–51 [Google Scholar]
  144. Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G. 144.  et al. 2007. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. PNAS 104:11002–7 [Google Scholar]
  145. Hoshino T, Okamoto M, Sakazaki Y, Kato S, Young HA, Aizawa H. 145.  2009. Role of proinflammatory cytokines IL-18 and IL-1β in bleomycin-induced lung injury in humans and mice. Am. J. Respir. Cell Mol. Biol. 41:661–70 [Google Scholar]
  146. Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO. 146.  et al. 2010. Bleomycin and IL-1β-mediated pulmonary fibrosis is IL-17A dependent. J. Exp. Med. 207:535–52 [Google Scholar]
  147. Navaratnam V, Fleming KM, West J, Smith CJ, Jenkins RG. 147.  et al. 2011. The rising incidence of idiopathic pulmonary fibrosis in the UK. Thorax 66:462–67 [Google Scholar]
  148. Stout-Delgado HW, Cho SJ, Chu SG, Mitzel DN, Villalba J. 148.  et al. 2016. Age-dependent susceptibility to pulmonary fibrosis is associated with NLRP3 inflammasome activation. Am. J. Respir. Cell Mol. Biol 55:252–63 [Google Scholar]
  149. Lee HC, Wei YH. 149.  2012. Mitochondria and aging. Adv. Exp. Med. Biol 942311–27 [Google Scholar]
  150. Rabinovitch M. 150.  2008. Molecular pathogenesis of pulmonary arterial hypertension. J. Clin. Investig. 118:2372–79 [Google Scholar]
  151. Villegas LR, Kluck D, Field C, Oberley-Deegan RE, Woods C. 151.  et al. 2013. Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3 inflammasome. Antioxid. Redox Signal. 18:1753–64 [Google Scholar]
  152. Cero FT, Hillestad V, Sjaastad I, Yndestad A, Aukrust P. 152.  et al. 2015. Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice. Am. J. Physiol. Lung. Cell Mol. Physiol. 309:L378–87 [Google Scholar]
  153. Rimessi A, Bezzerri V, Patergnani S, Marchi S, Cabrini G, Pinton P. 153.  2015. Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis. Nat. Commun. 6:6201 [Google Scholar]

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error