Skip to main content
SpringerLink
Log in

Activation of the Innate Immune Receptors: Guardians of the Micro Galaxy

Activation and Functions of the Innate Immune Receptors

  • Chapter
  • First Online:
Regulation of Inflammatory Signaling in Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1024))

Abstract

The families of innate immune receptors are the frontline responders to danger. These superheroes of the host immune systems populate innate immune cells, surveying the extracellular environment and the intracellular endolysosomal compartments and cytosol for exogenous and endogenous danger signals. As a collective the innate immune receptors recognise a wide array of stimuli, and in response they initiate specific signalling pathways leading to activation of transcriptional or proteolytic pathways and the production of inflammatory molecules to destroy foreign pathogens and/or resolve tissue injury. In this review, I will give an overview of the innate immune system and the activation and effector functions of the families of receptors it comprises. Current key concepts will be described throughout, including innate immune memory, formation of innate immune receptor signalosomes, inflammasome formation and pyroptosis, methods of extrinsic cell communication and examples of receptor cooperation. Finally, several open questions and future directions in the field of innate immunity will be presented and discussed.

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

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  1. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454(7203):428–435. doi:10.1038/nature07201

    Article  PubMed  CAS  Google Scholar 

  2. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820. doi:10.1016/j.cell.2010.01.022

    Article  PubMed  CAS  Google Scholar 

  3. Thaiss CA, Levy M, Suez J, Elinav E (2014) The interplay between the innate immune system and the microbiota. Curr Opin Immunol 26:41–48. doi:10.1016/j.coi.2013.10.016

    Article  PubMed  CAS  Google Scholar 

  4. Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, Paley MA, Antenus M, Williams KL, Erikson J, Wherry EJ, Artis D (2012) Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37(1):158–170. doi:10.1016/j.immuni.2012.04.011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Kawashima T, Kosaka A, Yan H, Guo Z, Uchiyama R, Fukui R, Kaneko D, Kumagai Y, You DJ, Carreras J, Uematsu S, Jang MH, Takeuchi O, Kaisho T, Akira S, Miyake K, Tsutsui H, Saito T, Nishimura I, Tsuji NM (2013) Double-stranded RNA of intestinal commensal but not pathogenic bacteria triggers production of protective interferon-beta. Immunity 38(6):1187–1197. doi:10.1016/j.immuni.2013.02.024

    Article  PubMed  CAS  Google Scholar 

  6. Broderick L, De Nardo D, Franklin BS, Hoffman HM, Latz E (2015) The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol 10:395–424. doi:10.1146/annurev-pathol-012414-040431

    Article  PubMed  CAS  Google Scholar 

  7. de Jesus AA, Canna SW, Liu Y, Goldbach-Mansky R (2015) Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. Annu Rev Immunol 33:823–874. doi:10.1146/annurev-immunol-032414-112227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Grateau G, Hentgen V, Stojanovic KS, Jeru I, Amselem S, Steichen O (2013) How should we approach classification of autoinflammatory diseases? Nat Rev Rheumatol 9(10):624–629. doi:10.1038/nrrheum.2013.101

    Article  PubMed  CAS  Google Scholar 

  9. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CC, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R (2014) Activated STING in a vascular and pulmonary syndrome. N Engl J Med 371(6):507–518. doi:10.1056/NEJMoa1312625

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Masters SL, Lagou V, Jeru I, Baker PJ, Van Eyck L, Parry DA, Lawless D, De Nardo D, Garcia-Perez JE, Dagley LF, Holley CL, Dooley J, Moghaddas F, Pasciuto E, Jeandel PY, Sciot R, Lyras D, Webb AI, Nicholson SE, De Somer L, van Nieuwenhove E, Ruuth-Praz J, Copin B, Cochet E, Medlej-Hashim M, Megarbane A, Schroder K, Savic S, Goris A, Amselem S, Wouters C, Liston A (2016) Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Sci Transl Med 8(332):332ra345. doi:10.1126/scitranslmed.aaf1471

    Article  CAS  Google Scholar 

  11. Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O'Neill LA, Xavier RJ (2016) Trained immunity: a program of innate immune memory in health and disease. Science 352(6284):aaf1098. doi:10.1126/science.aaf1098

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Weavers H, Evans IR, Martin P, Wood W (2016) Corpse engulfment generates a molecular memory that primes the macrophage inflammatory response. Cell 165(7):1658–1671. doi:10.1016/j.cell.2016.04.049

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A, Matarese F, Cheng SC, Ratter J, Berentsen K, van der Ent MA, Sharifi N, Janssen-Megens EM, Ter Huurne M, Mandoli A, van Schaik T, Ng A, Burden F, Downes K, Frontini M, Kumar V, Giamarellos-Bourboulis EJ, Ouwehand WH, van der Meer JW, Joosten LA, Wijmenga C, Martens JH, Xavier RJ, Logie C, Netea MG, Stunnenberg HG (2014) Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345(6204):1251086. doi:10.1126/science.1251086

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Gauthier ME, Du Pasquier L, Degnan BM (2010) The genome of the sponge Amphimedon Queenslandica provides new perspectives into the origin of toll-like and interleukin 1 receptor pathways. Evol Dev 12(5):519–533. doi:10.1111/j.1525-142X.2010.00436.x

    Article  PubMed  CAS  Google Scholar 

  15. Yuen B, Bayes JM, Degnan SM (2014) The characterization of sponge NLRs provides insight into the origin and evolution of this innate immune gene family in animals. Mol Biol Evol 31(1):106–120. doi:10.1093/molbev/mst174

    Article  PubMed  CAS  Google Scholar 

  16. Mourao-Sa D, Roy S, Blander JM (2013) Vita-PAMPs: signatures of microbial viability. Adv Exp Med Biol 785:1–8. doi:10.1007/978-1-4614-6217-0_1

    Article  PubMed  CAS  Google Scholar 

  17. Sander LE, Davis MJ, Boekschoten MV, Amsen D, Dascher CC, Ryffel B, Swanson JA, Muller M, Blander JM (2011) Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474(7351):385–389. doi:10.1038/nature10072

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Martinon F (2010) Mechanisms of uric acid crystal-mediated autoinflammation. Immunol Rev 233(1):218–232. doi:10.1111/j.0105-2896.2009.00860.x

    Article  PubMed  CAS  Google Scholar 

  19. West AP, Shadel GS (2017) Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol 17(6):363–375. doi:10.1038/nri.2017.21

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Liston A, Masters SL (2017) Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat Rev Immunol 17(3):208–214. doi:10.1038/nri.2016.151

    Article  PubMed  CAS  Google Scholar 

  21. Kagan JC, Magupalli VG, Wu H (2014) SMOCs: supramolecular organizing centres that control innate immunity. Nat Rev Immunol 14(12):821–826. doi:10.1038/nri3757

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Qiao Q, Wu H (2015) Supramolecular organizing centers (SMOCs) as signaling machines in innate immune activation. Sci China Life Sci 58(11):1067–1072. doi:10.1007/s11427-015-4951-z

    Article  PubMed  CAS  Google Scholar 

  23. Ferrao R, Wu H (2012) Helical assembly in the death domain (DD) superfamily. Curr Opin Struct Biol 22(2):241–247. doi:10.1016/j.sbi.2012.02.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. Dick MS, Sborgi L, Ruhl S, Hiller S, Broz P (2016) ASC filament formation serves as a signal amplification mechanism for inflammasomes. Nat Commun 7:11929. doi:10.1038/ncomms11929

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, Rosenberg S, Zhang J, Alnemri ES (2007) The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ 14(9):1590–1604. doi:10.1038/sj.cdd.4402194

    Article  PubMed  CAS  Google Scholar 

  27. 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  PubMed  CAS  Google Scholar 

  28. 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  PubMed  CAS  Google Scholar 

  29. Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang DC, Shao F (2016) Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535(7610):111–116. doi:10.1038/nature18590

    Article  PubMed  CAS  Google Scholar 

  30. Xu H, He X, Zheng H, Huang LJ, Hou F, Yu Z, de la Cruz MJ, Borkowski B, Zhang X, Chen ZJ, Jiang QX (2014a) Structural basis for the prion-like MAVS filaments in antiviral innate immunity. elife 3:e01489. doi:10.7554/eLife.01489

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen ZJ (2011) MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146(3):448–461. doi:10.1016/j.cell.2011.06.041

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. De Nardo D (2015) Toll-like receptors: activation, signalling and transcriptional modulation. Cytokine 74(2):181–189. doi:10.1016/j.cyto.2015.02.025

    Article  PubMed  CAS  Google Scholar 

  33. Lin SC, Lo YC, Wu H (2010) Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465(7300):885–890. doi:10.1038/nature09121

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Motshwene PG, Moncrieffe MC, Grossmann JG, Kao C, Ayaluru M, Sandercock AM, Robinson CV, Latz E, Gay NJ (2009) An oligomeric signaling platform formed by the toll-like receptor signal transducers MyD88 and IRAK-4. J Biol Chem 284(37):25404–25411. doi:10.1074/jbc.M109.022392

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Ferrao R, Zhou H, Shan Y, Liu Q, Li Q, Shaw DE, Li X, Wu H (2014) IRAK4 dimerization and trans-autophosphorylation are induced by Myddosome assembly. Mol Cell 55(6):891–903. doi:10.1016/j.molcel.2014.08.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Gay NJ, Gangloff M, O'Neill LA (2011) What the Myddosome structure tells us about the initiation of innate immunity. Trends Immunol 32(3):104–109. doi:10.1016/j.it.2010.12.005

    Article  PubMed  CAS  Google Scholar 

  37. Gay NJ, Symmons MF, Gangloff M, Bryant CE (2014) Assembly and localization of toll-like receptor signalling complexes. Nat Rev Immunol 14(8):546–558. doi:10.1038/nri3713

    Article  PubMed  CAS  Google Scholar 

  38. Hasan U, Chaffois C, Gaillard C, Saulnier V, Merck E, Tancredi S, Guiet C, Briere F, Vlach J, Lebecque S, Trinchieri G, Bates EE (2005) Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol 174(5):2942–2950

    Article  CAS  PubMed  Google Scholar 

  39. Hess NJ, Felicelli C, Grage J, Tapping RI (2017) TLR10 suppresses the activation and differentiation of monocytes with effects on DC-mediated adaptive immune responses. J Leukoc Biol 101(5):1245–1252. doi:10.1189/jlb.3A1116-492R

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Jiang S, Li X, Hess NJ, Guan Y, Tapping RI (2016) TLR10 is a negative regulator of both MyD88-dependent and -independent TLR signaling. J Immunol 196(9):3834–3841. doi:10.4049/jimmunol.1502599

    Article  PubMed  CAS  Google Scholar 

  41. Oosting M, Cheng SC, Bolscher JM, Vestering-Stenger R, Plantinga TS, Verschueren IC, Arts P, Garritsen A, van Eenennaam H, Sturm P, Kullberg BJ, Hoischen A, Adema GJ, van der Meer JW, Netea MG, Joosten LA (2014) Human TLR10 is an anti-inflammatory pattern-recognition receptor. Proc Natl Acad Sci U S A 111(42):E4478–E4484. doi:10.1073/pnas.1410293111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Regan T, Nally K, Carmody R, Houston A, Shanahan F, Macsharry J, Brint E (2013) Identification of TLR10 as a key mediator of the inflammatory response to Listeria monocytogenes in intestinal epithelial cells and macrophages. J Immunol 191(12):6084–6092. doi:10.4049/jimmunol.1203245

    Article  PubMed  CAS  Google Scholar 

  43. Gay NJ, Gangloff M (2007) Structure and function of toll receptors and their ligands. Annu Rev Biochem 76:141–165. doi:10.1146/annurev.biochem.76.060305.151318

    Article  PubMed  CAS  Google Scholar 

  44. Morr M, Takeuchi O, Akira S, Simon MM, Muhlradt PF (2002) Differential recognition of structural details of bacterial lipopeptides by toll-like receptors. Eur J Immunol 32(12):3337–3347. doi:10.1002/1521-4141(200212)32:12<3337::AID-IMMU3337>3.0.CO;2-#

    Article  PubMed  CAS  Google Scholar 

  45. Takeuchi O, Kawai T, Muhlradt PF, Morr M, Radolf JD, Zychlinsky A, Takeda K, Akira S (2001) Discrimination of bacterial lipoproteins by toll-like receptor 6. Int Immunol 13(7):933–940

    Article  CAS  PubMed  Google Scholar 

  46. Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, Modlin RL, Akira S (2002) Cutting edge: role of toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 169(1):10–14

    Article  CAS  PubMed  Google Scholar 

  47. Dillon S, Agrawal S, Banerjee K, Letterio J, Denning TL, Oswald-Richter K, Kasprowicz DJ, Kellar K, Pare J, van Dyke T, Ziegler S, Unutmaz D, Pulendran B (2006) Yeast zymosan, a stimulus for TLR2 and Dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. J Clin Invest 116(4):916–928. doi:10.1172/JCI27203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Yadav M, Schorey JS (2006) The beta-glucan receptor Dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 108(9):3168–3175. doi:10.1182/blood-2006-05-024406

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Andrade WA, Souza Mdo C, Ramos-Martinez E, Nagpal K, Dutra MS, Melo MB, Bartholomeu DC, Ghosh S, Golenbock DT, Gazzinelli RT (2013) Combined action of nucleic acid-sensing toll-like receptors and TLR11/TLR12 heterodimers imparts resistance to Toxoplasma gondii in mice. Cell Host Microbe 13(1):42–53. doi:10.1016/j.chom.2012.12.003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ (2010) CD36 ligands promote sterile inflammation through assembly of a toll-like receptor 4 and 6 heterodimer. Nat Immunol 11(2):155–161. doi:10.1038/ni.1836

    Article  PubMed  CAS  Google Scholar 

  51. Burns K, Martinon F, Esslinger C, Pahl H, Schneider P, Bodmer JL, Di Marco F, French L, Tschopp J (1998) MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem 273(20):12203–12209

    Article  CAS  PubMed  Google Scholar 

  52. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11(1):115–122

    Article  CAS  PubMed  Google Scholar 

  53. Bonham KS, Orzalli MH, Hayashi K, Wolf AI, Glanemann C, Weninger W, Iwasaki A, Knipe DM, Kagan JC (2014) A promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction. Cell 156(4):705–716. doi:10.1016/j.cell.2014.01.019

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA (2001) Mal (MyD88-adapter-like) is required for toll-like receptor-4 signal transduction. Nature 413(6851):78–83. doi:10.1038/35092578

    Article  PubMed  CAS  Google Scholar 

  55. Horng T, Barton GM, Flavell RA, Medzhitov R (2002) The adaptor molecule TIRAP provides signalling specificity for toll-like receptors. Nature 420(6913):329–333. doi:10.1038/nature01180

    Article  PubMed  CAS  Google Scholar 

  56. Horng T, Barton GM, Medzhitov R (2001) TIRAP: an adapter molecule in the toll signaling pathway. Nat Immunol 2(9):835–841. doi:10.1038/ni0901-835

    Article  CAS  PubMed  Google Scholar 

  57. Kagan JC, Medzhitov R (2006) Phosphoinositide-mediated adaptor recruitment controls toll-like receptor signaling. Cell 125(5):943–955. doi:10.1016/j.cell.2006.03.047

    Article  PubMed  CAS  Google Scholar 

  58. Dunne A, Ejdeback M, Ludidi PL, O'Neill LA, Gay NJ (2003) Structural complementarity of toll/interleukin-1 receptor domains in toll-like receptors and the adaptors mal and MyD88. J Biol Chem 278(42):41443–41451. doi:10.1074/jbc.M301742200

    Article  PubMed  CAS  Google Scholar 

  59. Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X (2001) IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B. J Biol Chem 276(45):41661–41667. doi:10.1074/jbc.M102262200

    Article  PubMed  CAS  Google Scholar 

  60. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A, Taya C, Taniguchi T (2005) Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434(7036):1035–1040. doi:10.1038/nature03547

    Article  CAS  PubMed  Google Scholar 

  61. Honda K, Yanai H, Mizutani T, Negishi H, Shimada N, Suzuki N, Ohba Y, Takaoka A, Yeh WC, Taniguchi T (2004) Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in toll-like receptor signaling. Proc Natl Acad Sci U S A 101(43):15416–15421. doi:10.1073/pnas.0406933101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, Takeuchi O, Akira S (2005) Interleukin-1 receptor-associated kinase-1 plays an essential role for toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med 201(6):915–923. doi:10.1084/jem.20042372

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya T (2003) TICAM-1, an adaptor molecule that participates in toll-like receptor 3-mediated interferon-beta induction. Nat Immunol 4(2):161–167. doi:10.1038/ni886

    Article  PubMed  CAS  Google Scholar 

  64. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S (2003a) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301(5633):640–643. doi:10.1126/science.1087262

    Article  PubMed  CAS  Google Scholar 

  65. Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira S (2002) Cutting edge: a novel toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the toll-like receptor signaling. J Immunol 169(12):6668–6672

    Article  CAS  PubMed  Google Scholar 

  66. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S (2003b) TRAM is specifically involved in the toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4(11):1144–1150. doi:10.1038/ni986

    Article  PubMed  CAS  Google Scholar 

  67. Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R (2008) TRAM couples endocytosis of toll-like receptor 4 to the induction of interferon-beta. Nat Immunol 9(4):361–368. doi:10.1038/ni1569

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC (2011) CD14 controls the LPS-induced endocytosis of toll-like receptor 4. Cell 147(4):868–880. doi:10.1016/j.cell.2011.09.051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the toll-like receptor signaling. J Immunol 171(8):4304–4310

    Article  CAS  PubMed  Google Scholar 

  70. Gohda J, Matsumura T, Inoue J (2004) Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol 173(5):2913–2917

    Article  CAS  PubMed  Google Scholar 

  71. 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(3):285–287. doi:10.1016/j.immuni.2008.02.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13(6):397–411. doi:10.1038/nri3452

    Article  PubMed  CAS  Google Scholar 

  73. Broxmeyer HE, Cooper S, Hangoc G, Chang CH (2006) Class II transactivator-mediated regulation of major histocompatibility complex class II antigen expression is important for hematopoietic progenitor cell suppression by chemokines and iron-binding proteins. Exp Hematol 34(8):1078–1084. doi:10.1016/j.exphem.2006.04.008

    Article  PubMed  CAS  Google Scholar 

  74. 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(5):836–847. doi:10.1038/cr.2012.56

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. 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  PubMed  PubMed Central  CAS  Google Scholar 

  76. 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  PubMed  PubMed Central  CAS  Google Scholar 

  77. 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(5):1045–1059. doi:10.1016/j.cell.2014.01.026

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Allen IC, Moore CB, Schneider M, Lei Y, Davis BK, Scull MA, Gris D, Roney KE, Zimmermann AG, Bowzard JB, Ranjan P, Monroe KM, Pickles RJ, Sambhara S, Ting JP (2011) NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-kappaB signaling pathways. Immunity 34(6):854–865. doi:10.1016/j.immuni.2011.03.026

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Guo H, Konig R, Deng M, Riess M, Mo J, Zhang L, Petrucelli A, Yoh SM, Barefoot B, Samo M, Sempowski GD, Zhang A, Colberg-Poley AM, Feng H, Lemon SM, Liu Y, Zhang Y, Wen H, Zhang Z, Damania B, Tsao LC, Wang Q, Su L, Duncan JA, Chanda SK, Ting JP (2016) NLRX1 sequesters STING to negatively regulate the interferon response, thereby facilitating the replication of HIV-1 and DNA viruses. Cell Host Microbe 19(4):515–528. doi:10.1016/j.chom.2016.03.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Zhang L, Mo J, Swanson KV, Wen H, Petrucelli A, Gregory SM, Zhang Z, Schneider M, Jiang Y, Fitzgerald KA, Ouyang S, Liu ZJ, Damania B, Shu HB, Duncan JA, Ting JP (2014) NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 40(3):329–341. doi:10.1016/j.immuni.2014.01.010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, Ogura Y, Kawasaki A, Fukase K, Kusumoto S, Valvano MA, Foster SJ, Mak TW, Nunez G, Inohara N (2003) An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 4(7):702–707. doi:10.1038/ni945

    Article  PubMed  CAS  Google Scholar 

  82. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, Tedin K, Taha MK, Labigne A, Zahringer U, Coyle AJ, DiStefano PS, Bertin J, Sansonetti PJ, Philpott DJ (2003a) Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300(5625):1584–1587. doi:10.1126/science.1084677

    Article  PubMed  CAS  Google Scholar 

  83. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ (2003b) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278(11):8869–8872. doi:10.1074/jbc.C200651200

    Article  PubMed  CAS  Google Scholar 

  84. Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE (2014) NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol 14(1):9–23. doi:10.1038/nri3565

    Article  PubMed  CAS  Google Scholar 

  85. Strober W, Murray PJ, Kitani A, Watanabe T (2006) Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 6(1):9–20. doi:10.1038/nri1747

    Article  PubMed  CAS  Google Scholar 

  86. 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. 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(1):e01117–e01113. doi:10.1128/mBio.01117-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. 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(1):155–164. doi:10.1016/j.cmet.2015.09.024

    Article  PubMed  CAS  Google Scholar 

  89. D'Osualdo A, Reed JC (2012) NLRP1, a regulator of innate immunity associated with vitiligo. Pigment Cell Melanoma Res 25(1):5–8. doi:10.1111/j.1755-148X.2011.00942.x

    Article  PubMed  CAS  Google Scholar 

  90. Jin Y, Riccardi SL, Gowan K, Fain PR, Spritz RA (2010) Fine-mapping of vitiligo susceptibility loci on chromosomes 7 and 9 and interactions with NLRP1 (NALP1). J Invest Dermatol 130(3):774–783. doi:10.1038/jid.2009.273

    Article  PubMed  CAS  Google Scholar 

  91. 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-1beta processing via the NLRP1 inflammasome. Proc Natl Acad Sci U S A 110(8):2952–2956. doi:10.1073/pnas.1222808110

    Article  PubMed  PubMed Central  Google Scholar 

  92. Zhong FL, Mamai O, Sborgi L, Boussofara L, Hopkins R, Robinson K, Szeverenyi I, Takeichi T, Balaji R, Lau A, Tye H, Roy K, Bonnard C, Ahl PJ, Jones LA, Baker P, Lacina L, Otsuka A, Fournie PR, Malecaze F, Lane EB, Akiyama M, Kabashima K, Connolly JE, Masters SL, Soler VJ, Omar SS, McGrath JA, Nedelcu R, Gribaa M, Denguezli M, Saad A, Hiller S, Reversade B (2016) Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation. Cell 167(1):187–202. e117. doi:10.1016/j.cell.2016.09.001

    Article  PubMed  CAS  Google Scholar 

  93. Broz P, Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 16(7):407–420. doi:10.1038/nri.2016.58

    Article  PubMed  CAS  Google Scholar 

  94. De Nardo D, De Nardo CM, Latz E (2014a) New insights into mechanisms controlling the NLRP3 inflammasome and its role in lung disease. Am J Pathol 184(1):42–54. doi:10.1016/j.ajpath.2013.09.007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Conos SA, Chen KW, De Nardo D, Hara H, Whitehead L, Nunez G, Masters SL, Murphy JM, Schroder K, Vaux DL, Lawlor KE, Lindqvist LM, Vince JE (2017) Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. Proc Natl Acad Sci U S A 114(6):E961–E969. doi:10.1073/pnas.1613305114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. 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  PubMed  PubMed Central  CAS  Google Scholar 

  97. Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J (2007) Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 14(9):1583–1589. doi:10.1038/sj.cdd.4402195

    Article  PubMed  CAS  Google Scholar 

  98. Halff EF, Diebolder CA, Versteeg M, Schouten A, Brondijk TH, Huizinga EG (2012) Formation and structure of a NAIP5-NLRC4 inflammasome induced by direct interactions with conserved N- and C-terminal regions of flagellin. J Biol Chem 287(46):38460–38472. doi:10.1074/jbc.M112.393512

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Vance RE (2015) The NAIP/NLRC4 inflammasomes. Curr Opin Immunol 32:84–89. doi:10.1016/j.coi.2015.01.010

    Article  PubMed  CAS  Google Scholar 

  100. 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(7366):596–600. doi:10.1038/nature10510

    Article  PubMed  CAS  Google Scholar 

  101. 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(6259):399–404. doi:10.1126/science.aac5489

    Article  PubMed  CAS  Google Scholar 

  102. 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(6259):404–409. doi:10.1126/science.aac5789

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Matusiak M, Van Opdenbosch N, Vande Walle L, Sirard JC, Kanneganti TD, Lamkanfi M (2015) Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5. Proc Natl Acad Sci U S A 112(5):1541–1546. doi:10.1073/pnas.1417945112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Qu Y, Misaghi S, Izrael-Tomasevic A, Newton K, Gilmour LL, Lamkanfi M, Louie S, Kayagaki N, Liu J, Komuves L, Cupp JE, Arnott D, Monack D, Dixit VM (2012) Phosphorylation of NLRC4 is critical for inflammasome activation. Nature 490(7421):539–542. doi:10.1038/nature11429

    Article  PubMed  CAS  Google Scholar 

  105. 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(3):464–476. doi:10.1016/j.immuni.2012.02.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. 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. doi:10.1016/j.molimm.2015.06.013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. 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(1):96–107. doi:10.1016/j.immuni.2012.07.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Yu JW, Wu J, Zhang Z, Datta P, Ibrahimi I, Taniguchi S, Sagara J, Fernandes-Alnemri T, Alnemri ES (2006) Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization. Cell Death Differ 13(2):236–249. doi:10.1038/sj.cdd.4401734

    Article  PubMed  CAS  Google Scholar 

  109. Xu H, Yang J, Gao W, Li L, Li P, Zhang L, Gong YN, Peng X, Xi JJ, Chen S, Wang F, Shao F (2014b) Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 513(7517):237–241. doi:10.1038/nature13449

    Article  PubMed  CAS  Google Scholar 

  110. Park YH, Wood G, Kastner DL, Chae JJ (2016) Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 17(8):914–921. doi:10.1038/ni.3457

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Kang DC, Gopalkrishnan RV, Wu Q, Jankowsky E, Pyle AM, Fisher PB (2002) mda-5: an interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc Natl Acad Sci U S A 99(2):637–642. doi:10.1073/pnas.022637199

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O (2010) LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc Natl Acad Sci U S A 107(4):1512–1517. doi:10.1073/pnas.0912986107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5(7):730–737. doi:10.1038/ni1087

    Article  PubMed  CAS  Google Scholar 

  114. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441(7089):101–105. doi:10.1038/nature04734

    Article  PubMed  CAS  Google Scholar 

  115. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S (2008) Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205(7):1601–1610. doi:10.1084/jem.20080091

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G (2006) 5’-Triphosphate RNA is the ligand for RIG-I. Science 314(5801):994–997. doi:10.1126/science.1132505

    Article  PubMed  Google Scholar 

  117. Rothenfusser S, Goutagny N, DiPerna G, Gong M, Monks BG, Schoenemeyer A, Yamamoto M, Akira S, Fitzgerald KA (2005) The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol 175(8):5260–5268

    Article  CAS  PubMed  Google Scholar 

  118. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S (2005) IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6(10):981–988. doi:10.1038/ni1243

    Article  PubMed  CAS  Google Scholar 

  119. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437(7062):1167–1172. doi:10.1038/nature04193

    Article  PubMed  CAS  Google Scholar 

  120. Seth RB, Sun L, Ea CK, Chen ZJ (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122(5):669–682. doi:10.1016/j.cell.2005.08.012

    Article  PubMed  CAS  Google Scholar 

  121. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB (2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19(6):727–740. doi:10.1016/j.molcel.2005.08.014

    Article  PubMed  CAS  Google Scholar 

  122. Kawai T, Akira S (2008) Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci 1143:1–20. doi:10.1196/annals.1443.020

    Article  PubMed  CAS  Google Scholar 

  123. Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, Gordon S (2003) Dectin-1 mediates the biological effects of beta-glucans. J Exp Med 197(9):1119–1124. doi:10.1084/jem.20021890

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Gazi U, Rosas M, Singh S, Heinsbroek S, Haq I, Johnson S, Brown GD, Williams DL, Taylor PR, Martinez-Pomares L (2011) Fungal recognition enhances mannose receptor shedding through Dectin-1 engagement. J Biol Chem 286(10):7822–7829. doi:10.1074/jbc.M110.185025

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Ishikawa E, Ishikawa T, Morita YS, Toyonaga K, Yamada H, Takeuchi O, Kinoshita T, Akira S, Yoshikai Y, Yamasaki S (2009a) Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J Exp Med 206(13):2879–2888. doi:10.1084/jem.20091750

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Kerrigan AM, Brown GD (2010) Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifs. Immunol Rev 234(1):335–352. doi:10.1111/j.0105-2896.2009.00882.x

    Article  PubMed  CAS  Google Scholar 

  127. Geijtenbeek TB, Gringhuis SI (2009) Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol 9(7):465–479. doi:10.1038/nri2569

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  128. Gross O, Gewies A, Finger K, Schafer M, Sparwasser T, Peschel C, Forster I, Ruland J (2006) Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442(7103):651–656. doi:10.1038/nature04926

    Article  CAS  PubMed  Google Scholar 

  129. Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger 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(3):266–272. doi:10.1038/ni.1702

    Article  PubMed  CAS  Google Scholar 

  130. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES (2009) AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458(7237):509–513. doi:10.1038/nature07710

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. 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(7237):514–518. doi:10.1038/nature07725

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, Hardy LL, Garceau V, Sweet MJ, Ross IL, Hume DA, Stacey KJ (2009) HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323(5917):1057–1060. doi:10.1126/science.1169841

    Article  PubMed  CAS  Google Scholar 

  133. 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(5):395–402. doi:10.1038/ni.1864

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Hu B, Jin C, Li HB, Tong J, Ouyang X, Cetinbas NM, Zhu S, Strowig T, Lam FC, Zhao C, Henao-Mejia J, Yilmaz O, Fitzgerald KA, Eisenbarth SC, Elinav E, Flavell RA (2016) The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science 354(6313):765–768. doi:10.1126/science.aaf7532

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Jin T, Perry A, Jiang J, Smith P, Curry JA, Unterholzner L, Jiang Z, Horvath G, Rathinam VA, Johnstone RW, Hornung V, Latz E, Bowie AG, Fitzgerald KA, Xiao TS (2012) Structures of the HIN domain: DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36(4):561–571. doi:10.1016/j.immuni.2012.02.014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Lu A, Li Y, Yin Q, Ruan J, Yu X, Egelman E, Wu H (2015) Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2. Cell Discov 1. doi:10.1038/celldisc.2015.13

  137. Li XD, Wu J, Gao D, Wang H, Sun L, Chen ZJ (2013) Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341(6152):1390–1394. doi:10.1126/science.1244040

    Article  PubMed  CAS  Google Scholar 

  138. Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455(7213):674–678. doi:10.1038/nature07317

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Ishikawa H, Ma Z, Barber GN (2009b) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461(7265):788–792. doi:10.1038/nature08476

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Sun L, Wu J, Du F, Chen X, Chen ZJ (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339(6121):786–791. doi:10.1126/science.1232458

    Article  PubMed  CAS  Google Scholar 

  141. Wu J, Sun L, Chen X, Du F, Shi H, Chen C, Chen ZJ (2013) Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339(6121):826–830. doi:10.1126/science.1229963

    Article  PubMed  CAS  Google Scholar 

  142. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Rohl I, Hopfner KP, Ludwig J, Hornung V (2013a) cGAS produces a 2’-5’-linked cyclic dinucleotide second messenger that activates STING. Nature 498(7454):380–384. doi:10.1038/nature12306

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M, Witte G, Hornung V, Hopfner KP (2013) Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498(7454):332–337. doi:10.1038/nature12305

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Diner EJ, Burdette DL, Wilson SC, Monroe KM, Kellenberger CA, Hyodo M, Hayakawa Y, Hammond MC, Vance RE (2013) The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep 3(5):1355–1361. doi:10.1016/j.celrep.2013.05.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, Serganov AA, Liu Y, Jones RA, Hartmann G, Tuschl T, Patel DJ (2013a) Cyclic [G(2’,5’)pA(3’,5’)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153(5):1094–1107. doi:10.1016/j.cell.2013.04.046

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Zhang X, Shi H, Wu J, Zhang X, Sun L, Chen C, Chen ZJ (2013) Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol Cell 51(2):226–235. doi:10.1016/j.molcel.2013.05.022

    Article  PubMed  CAS  Google Scholar 

  147. Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, Tuting T, Hartmann G, Barchet W (2013) Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39(3):482–495. doi:10.1016/j.immuni.2013.08.004

    Article  PubMed  CAS  Google Scholar 

  148. 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  PubMed  PubMed Central  CAS  Google Scholar 

  149. Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V (2014) TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol 192(12):5993–5997. doi:10.4049/jimmunol.1400737

    Article  PubMed  CAS  Google Scholar 

  150. Ahn J, Gutman D, Saijo S, Barber GN (2012) STING manifests self DNA-dependent inflammatory disease. Proc Natl Acad Sci U S A 109(47):19386–19391. doi:10.1073/pnas.1215006109

    Article  PubMed  PubMed Central  Google Scholar 

  151. Gray EE, Treuting PM, Woodward JJ, Stetson DB (2015) Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutieres syndrome. J Immunol 195(5):1939–1943. doi:10.4049/jimmunol.1500969

    Article  PubMed  CAS  Google Scholar 

  152. Pokatayev V, Hasin N, Chon H, Cerritelli SM, Sakhuja K, Ward JM, Morris HD, Yan N, Crouch RJ (2016) RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J Exp Med 213(3):329–336. doi:10.1084/jem.20151464

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Herzner AM, Hagmann CA, Goldeck M, Wolter S, Kubler K, Wittmann S, Gramberg T, Andreeva L, Hopfner KP, Mertens C, Zillinger T, Jin T, Xiao TS, Bartok E, Coch C, Ackermann D, Hornung V, Ludwig J, Barchet W, Hartmann G, Schlee M (2015) Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA. Nat Immunol 16(10):1025–1033. doi:10.1038/ni.3267

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Mankan AK, Schmidt T, Chauhan D, Goldeck M, Honing K, Gaidt M, Kubarenko AV, Andreeva L, Hopfner KP, Hornung V (2014) Cytosolic RNA:DNA hybrids activate the cGAS-STING axis. EMBO J 33(24):2937–2946. doi:10.15252/embj.201488726

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Gao P, Ascano M, Zillinger T, Wang W, Dai P, Serganov AA, Gaffney BL, Shuman S, Jones RA, Deng L, Hartmann G, Barchet W, Tuschl T, Patel DJ (2013b) Structure-function analysis of STING activation by c[G(2’,5’)pA(3’,5’)p] and targeting by antiviral DMXAA. Cell 154(4):748–762. doi:10.1016/j.cell.2013.07.023

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Shu C, Yi G, Watts T, Kao CC, Li P (2012) Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system. Nat Struct Mol Biol 19(7):722–724. doi:10.1038/nsmb.2331

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE (2011) STING is a direct innate immune sensor of cyclic di-GMP. Nature 478(7370):515–518. doi:10.1038/nature10429

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Barber GN (2014) STING-dependent cytosolic DNA sensing pathways. Trends Immunol 35(2):88–93. doi:10.1016/j.it.2013.10.010

    Article  PubMed  CAS  Google Scholar 

  159. de Weerd NA, Samarajiwa SA, Hertzog PJ (2007) Type I interferon receptors: biochemistry and biological functions. J Biol Chem 282(28):20053–20057. doi:10.1074/jbc.R700006200

    Article  PubMed  CAS  Google Scholar 

  160. Schoggins JW (2014) Interferon-stimulated genes: roles in viral pathogenesis. Curr Opin Virol 6:40–46. doi:10.1016/j.coviro.2014.03.006

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  161. Kasper CA, Sorg I, Schmutz C, Tschon T, Wischnewski H, Kim ML, Arrieumerlou C (2010) Cell-cell propagation of NF-kappaB transcription factor and MAP kinase activation amplifies innate immunity against bacterial infection. Immunity 33(5):804–816. doi:10.1016/j.immuni.2010.10.015

    Article  PubMed  CAS  Google Scholar 

  162. Patel SJ, King KR, Casali M, Yarmush ML (2009) DNA-triggered innate immune responses are propagated by gap junction communication. Proc Natl Acad Sci U S A 106(31):12867–12872. doi:10.1073/pnas.0809292106

    Article  PubMed  PubMed Central  Google Scholar 

  163. Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, Hornung V (2013b) Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503(7477):530–534. doi:10.1038/nature12640

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Xu S, Ducroux A, Ponnurangam A, Vieyres G, Franz S, Musken M, Zillinger T, Malassa A, Ewald E, Hornung V, Barchet W, Haussler S, Pietschmann T, Goffinet C (2016) cGAS-mediated innate immunity spreads intercellularly through HIV-1 Env-induced membrane fusion sites. Cell Host Microbe 20(4):443–457. doi:10.1016/j.chom.2016.09.003

    Article  PubMed  CAS  Google Scholar 

  165. Bridgeman A, Maelfait J, Davenne T, Partridge T, Peng Y, Mayer A, Dong T, Kaever V, Borrow P, Rehwinkel J (2015) Viruses transfer the antiviral second messenger cGAMP between cells. Science 349(6253):1228–1232. doi:10.1126/science.aab3632

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Gentili M, Kowal J, Tkach M, Satoh T, Lahaye X, Conrad C, Boyron M, Lombard B, Durand S, Kroemer G, Loew D, Dalod M, Thery C, Manel N (2015) Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 349(6253):1232–1236. doi:10.1126/science.aab3628

    Article  PubMed  CAS  Google Scholar 

  167. Baroja-Mazo A, Martin-Sanchez F, Gomez AI, Martinez CM, Amores-Iniesta J, Compan V, Barbera-Cremades M, Yague J, Ruiz-Ortiz E, Anton J, Bujan S, Couillin I, Brough D, Arostegui JI, Pelegrin P (2014) The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 15(8):738–748. doi:10.1038/ni.2919

    Article  PubMed  CAS  Google Scholar 

  168. 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, Kastenmuller W, Latz E (2014) The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat Immunol 15(8):727–737. doi:10.1038/ni.2913

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Kim S, Bauernfeind F, Ablasser A, Hartmann G, Fitzgerald KA, Latz E, Hornung V (2010) Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome. Eur J Immunol 40(6):1545–1551. doi:10.1002/eji.201040425

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Ozoren N, Masumoto J, Franchi L, Kanneganti TD, Body-Malapel M, Erturk I, Jagirdar R, Zhu L, Inohara N, Bertin J, Coyle A, Grant EP, Nunez G (2006) Distinct roles of TLR2 and the adaptor ASC in IL-1beta/IL-18 secretion in response to Listeria monocytogenes. J Immunol 176(7):4337–4342

    Article  PubMed  Google Scholar 

  171. Sauer JD, Witte CE, Zemansky J, Hanson B, Lauer P, Portnoy DA (2010) Listeria monocytogenes triggers AIM2-mediated pyroptosis upon infrequent bacteriolysis in the macrophage cytosol. Cell Host Microbe 7(5):412–419. doi:10.1016/j.chom.2010.04.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Wu J, Fernandes-Alnemri T, Alnemri ES (2010) Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. J Clin Immunol 30(5):693–702. doi:10.1007/s10875-010-9425-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. 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  PubMed  CAS  Google Scholar 

  174. Casson CN, Yu J, Reyes VM, Taschuk FO, Yadav A, Copenhaver AM, Nguyen HT, Collman RG, Shin S (2015) Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens. Proc Natl Acad Sci U S A 112(21):6688–6693. doi:10.1073/pnas.1421699112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. 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  PubMed  PubMed Central  CAS  Google Scholar 

  176. 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 341(6151):1246–1249. doi:10.1126/science.1240248

    Article  PubMed  CAS  Google Scholar 

  177. 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 

  178. Schmid-Burgk JL, Gaidt MM, Schmidt T, Ebert TS, Bartok E, Hornung V (2015) Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells. Eur J Immunol 45(10):2911–2917. doi:10.1002/eji.201545523

    Article  PubMed  CAS  Google Scholar 

  179. 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

    Article  PubMed  CAS  Google Scholar 

  180. Vigano 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

    Article  PubMed  CAS  Google Scholar 

  181. Meunier E, Dick MS, Dreier RF, Schurmann N, Kenzelmann Broz D, Warming S, Roose-Girma M, Bumann D, Kayagaki N, Takeda K, Yamamoto M, Broz P (2014) Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases. Nature 509(7500):366–370. doi:10.1038/nature13157

    Article  PubMed  CAS  Google Scholar 

  182. Man SM, Karki R, Malireddi RK, Neale G, Vogel P, Yamamoto M, Lamkanfi M, Kanneganti TD (2015) The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nat Immunol 16(5):467–475. doi:10.1038/ni.3118

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Man SM, Karki R, Sasai M, Place DE, Kesavardhana S, Temirov J, Frase S, Zhu Q, Malireddi RK, Kuriakose T, Peters JL, Neale G, Brown SA, Yamamoto M, Kanneganti TD (2016) IRGB10 liberates bacterial Ligands for sensing by the AIM2 and Caspase-11-NLRP3 inflammasomes. Cell 167(2):382–396. e317. doi:10.1016/j.cell.2016.09.012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Meunier E, Wallet P, Dreier RF, Costanzo S, Anton L, Ruhl S, Dussurgey S, Dick MS, Kistner A, Rigard M, Degrandi D, Pfeffer K, Yamamoto M, Henry T, Broz P (2015) Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida. Nat Immunol 16(5):476–484. doi:10.1038/ni.3119

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Bekkering S, Joosten LA, van der Meer JW, Netea MG, Riksen NP (2015) The epigenetic memory of monocytes and macrophages as a novel drug target in atherosclerosis. Clin Ther 37(4):914–923. doi:10.1016/j.clinthera.2015.01.008

    Article  PubMed  CAS  Google Scholar 

  186. Blok BA, Arts RJ, van Crevel R, Benn CS, Netea MG (2015) Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukoc Biol 98(3):347–356. doi:10.1189/jlb.5RI0315-096R

    Article  PubMed  CAS  Google Scholar 

  187. De Nardo D, Labzin LI, Kono H, Seki R, Schmidt SV, Beyer M, Xu D, Zimmer S, Lahrmann C, Schildberg FA, Vogelhuber J, Kraut M, Ulas T, Kerksiek A, Krebs W, Bode N, Grebe A, Fitzgerald ML, Hernandez NJ, Williams BR, Knolle P, Kneilling M, Rocken M, Lutjohann D, Wright SD, Schultze JL, Latz E (2014b) High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nat Immunol 15(2):152–160. doi:10.1038/ni.2784

    Article  PubMed  CAS  Google Scholar 

  188. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, Ganesan H, Nino-Castro A, Mallmann MR, Labzin L, Theis H, Kraut M, Beyer M, Latz E, Freeman TC, Ulas T, Schultze JL (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40(2):274–288. doi:10.1016/j.immuni.2014.01.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. 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  PubMed  CAS  Google Scholar 

  190. Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F, Robertson AA, Cooper MA, Graf T, Hornung V (2016) Human monocytes engage an alternative inflammasome pathway. Immunity 44(4):833–846. doi:10.1016/j.immuni.2016.01.012

    Article  PubMed  CAS  Google Scholar 

  191. Conos SA, Lawlor KE, Vaux DL, Vince JE, Lindqvist LM (2016) Cell death is not essential for caspase-1-mediated interleukin-1beta activation and secretion. Cell Death Differ 23(11):1827–1838. doi:10.1038/cdd.2016.69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Sun J, Li N, Oh KS, Dutta B, Vayttaden SJ, Lin B, Ebert TS, De Nardo D, Davis J, Bagirzadeh R, Lounsbury NW, Pasare C, Latz E, Hornung V, Fraser ID (2016) Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use. Sci Signal 9(409):ra3. doi:10.1126/scisignal.aab2191

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

I am grateful to C.M. De Nardo for proofreading of the manuscript. I acknowledge the exceptional work by many investigators in the field who were not cited here due to space limitations.

Author information

Authors and Affiliations

  1. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia

    Dominic De Nardo

  2. Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia

    Dominic De Nardo

Authors
  1. Dominic De Nardo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dominic De Nardo .

Editor information

Editors and Affiliations

  1. Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Dakang Xu

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

De Nardo, D. (2017). Activation of the Innate Immune Receptors: Guardians of the Micro Galaxy. In: Xu, D. (eds) Regulation of Inflammatory Signaling in Health and Disease. Advances in Experimental Medicine and Biology, vol 1024. Springer, Singapore. https://doi.org/10.1007/978-981-10-5987-2_1

Download citation

Publish with us

Policies and ethics

Search

Navigation