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The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses

Nature Immunology volume 11, pages 395–402 (2010)Cite this article

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Abstract

Inflammasomes regulate the activity of caspase-1 and the maturation of interleukin 1β (IL-1β) and IL-18. AIM2 has been shown to bind DNA and engage the caspase-1-activating adaptor protein ASC to form a caspase-1-activating inflammasome. Using Aim2-deficient mice, we identify a central role for AIM2 in regulating caspase-1-dependent maturation of IL-1β and IL-18, as well as pyroptosis, in response to synthetic double-stranded DNA. AIM2 was essential for inflammasome activation in response to Francisella tularensis, vaccinia virus and mouse cytomegalovirus and had a partial role in the sensing of Listeria monocytogenes. Moreover, production of IL-18 and natural killer cell–dependent production of interferon-γ, events critical in the early control of virus replication, were dependent on AIM2 during mouse cytomegalovirus infection in vivo. Collectively, our observations demonstrate the importance of AIM2 in the sensing of both bacterial and viral pathogens and in triggering innate immunity.

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Figure 1: Characterization of Aim2 gene-trap mice.
Figure 2: AIM2 is essential for inflammasome activation by DNA.
Figure 3: AIM2-deficient cells respond normally to stimuli that activate other inflammasomes.
Figure 4: Production and signaling of type I interferons remain intact in AIM2-deficient cells.
Figure 5: AIM2 mediates inflammasome activation in response to bacterial pathogens.
Figure 6: AIM2 is essential for inflammasome activation by DNA viruses.
Figure 7: AIM2- and ASC-dependent IL-18 production and NK cell IFN-γ production.

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References

  1. Kawai, T. & Akira, S. Toll-like receptor and RIG-I-like receptor signaling. Ann. NY Acad. Sci. 1143, 1–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Takeda, K. & Akira, S. Toll-like receptors in innate immunity. Int. Immunol. 17, 1–14 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Huysamen, C. & Brown, G.D. The fungal pattern recognition receptor, Dectin-1, and the associated cluster of C-type lectin-like receptors. FEMS Microbiol. Lett. 290, 121–128 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Yoneyama, M. & Fujita, T. RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity. Cytokine Growth Factor Rev. 18, 545–551 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Takaoka, A. et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Chiu, Y.H., Macmillan, J.B. & Chen, Z.J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576–591 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ablasser, A. et al. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III–transcribed RNA intermediate. Nat. Immunol. 10, 1065–1072 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Roberts, T.L. et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323, 1057–1060 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fernandes-Alnemri, T., Yu, J.W., Datta, P., Wu, J. & Alnemri, E.S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature (2009).

  12. Burckstummer, T. et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat. Immunol. 10, 266–272 (2009).

    Article  PubMed  Google Scholar 

  13. Dinarello, C.A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Dinarello, C.A., Novick, D., Rubinstein, M. & Lonnemann, G. Interleukin 18 and interleukin 18 binding protein: possible role in immunosuppression of chronic renal failure. Blood Purif. 21, 258–270 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Boyden, E.D. & Dietrich, W.F. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat. Genet. 38, 240–244 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Latz, E. The inflammasomes: mechanisms of activation and function. Curr. Opin. Immunol. 22, 28–33 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Miao, E.A. et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc. Natl. Acad. Sci. USA 107, 3076–3080 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ludlow, L.E., Johnstone, R.W. & Clarke, C.J. The HIN-200 family: more than interferon-inducible genes? Exp. Cell Res. 308, 1–17 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Fernandes-Alnemri, T. et al. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 14, 1590–1604 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Poeck, H. et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1β production. Nat. Immunol. 11, 63–69 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Landolfo, S., Gariglio, M., Gribaudo, G. & Lembo, D. The Ifi 200 genes: an emerging family of IFN-inducible genes. Biochimie 80, 721–728 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Cole, L.E. et al. Macrophage proinflammatory response to Francisella tularensis live vaccine strain requires coordination of multiple signaling pathways. J. Immunol. 180, 6885–6891 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Henry, T., Brotcke, A., Weiss, D.S., Thompson, L.J. & Monack, D.M. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J. Exp. Med. 204, 987–994 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Elkins, K.L., Cowley, S.C. & Bosio, C.M. Innate and adaptive immunity to Francisella. Ann. NY Acad. Sci. 1105, 284–324 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Mariathasan, S., Weiss, D.S., Dixit, V.M. & Monack, D.M. Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. J. Exp. Med. 202, 1043–1049 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cole, L.E. et al. Toll-like receptor 2-mediated signaling requirements for Francisella tularensis live vaccine strain infection of murine macrophages. Infect. Immun. 75, 4127–4137 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lamkanfi, M. & Dixit, V.M. Inflammasomes: guardians of cytosolic sanctity. Immunol. Rev. 227, 95–105 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Kanneganti, T.D. et al. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26, 433–443 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Li, H., Nookala, S., Bina, X.R., Bina, J.E. & Re, F. Innate immune response to Francisella tularensis is mediated by TLR2 and caspase-1 activation. J. Leukoc. Biol. 80, 766–773 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Meixenberger, K. et al. Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1β, depending on listeriolysin O and NLRP3. J. Immunol. 184, 922–930 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Franchi, L., Kanneganti, T.D., Dubyak, G.R. & Nunez, G. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. J. Biol. Chem. 282, 18810–18818 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Warren, S.E., Mao, D.P., Rodriguez, A.E., Miao, E.A. & Aderem, A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J. Immunol. 180, 7558–7564 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Dinarello, C.A. Biologic basis for interleukin-1 in disease. Blood 87, 2095–2147 (1996).

    CAS  PubMed  Google Scholar 

  35. Pien, G.C. & Biron, C.A. Compartmental differences in NK cell responsiveness to IL-12 during lymphocytic choriomeningitis virus infection. J. Immunol. 164, 994–1001 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Daniels, K.A. et al. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194, 29–44 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hornung, V. & Latz, E. Intracellular DNA recognition. Nat. Rev. Immunol. 10, 123–130 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Ishikawa, H., Ma, Z. & Barber, G.N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fitzgerald, K.A. et al. IKKɛ and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4, 491–496 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Ichinohe, T., Lee, H.K., Ogura, Y., Flavell, R. & Iwasaki, A. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J. Exp. Med. 206, 79–87 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Labow, M. et al. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. J. Immunol. 159, 2452–2461 (1997).

    CAS  PubMed  Google Scholar 

  42. Alcami, A. & Smith, G.L. A soluble receptor for interleukin-1 beta encoded by vaccinia virus: a novel mechanism of virus modulation of the host response to infection. Cell 71, 153–167 (1992).

    Article  CAS  PubMed  Google Scholar 

  43. Smith, G.L. & Chan, Y.S. Two vaccinia virus proteins structurally related to the interleukin-1 receptor and the immunoglobulin superfamily. J. Gen. Virol. 72, 511–518 (1991).

    Article  CAS  PubMed  Google Scholar 

  44. Johnston, J.B. et al. A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection. Immunity 23, 587–598 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Henry, T. & Monack, D.M. Activation of the inflammasome upon Francisella tularensis infection: interplay of innate immune pathways and virulence factors. Cell. Microbiol. 9, 2543–2551 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Scalzo, A.A. et al. Genetic mapping of Cmv1 in the region of mouse chromosome 6 encoding the NK gene complex-associated loci Ly49 and musNKR-P1. Genomics 27, 435–441 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. McVicar, D.W. et al. Aberrant DAP12 signaling in the 129 strain of mice: implications for the analysis of gene-targeted mice. J. Immunol. 169, 1721–1728 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Brown, M.G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Lee, S.H. et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat. Genet. 28, 42–45 (2001).

    CAS  PubMed  Google Scholar 

  50. Elkins, K.L., Winegar, R.K., Nacy, C.A. & Fortier, A.H. Introduction of Francisella tularensis at skin sites induces resistance to infection and generation of protective immunity. Microb. Pathog. 13, 417–421 (1992).

    Article  CAS  PubMed  Google Scholar 

  51. Rathinam, V.A., Hoag, K.A. & Mansfield, L.S. Dendritic cells from C57BL/6 mice undergo activation and induce Th1-effector cell responses against Campylobacter jejuni. Microbes Infect. 10, 1316–1324 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Roberts, Z.J. et al. The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis. J. Exp. Med. 204, 1559–1569 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bukowski, J.F., Woda, B.A. & Welsh, R.M. Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice. J. Virol. 52, 119–128 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank R. Barbalat (University of California at Berkeley) and G. Barton (University of California at Berkeley) for vaccinia virus; R. Welsh (University of Massachusetts Medical School) for mCMV; D. Knipe (Harvard Medical School) for HSV-1; M. O'Riordan (University of Michigan) for S. typhimurium; V. Boyartchuk (University of Massachusetts Medical School) for L. monocytogenes; T. Taniguchi (University of Tokyo) for Irf3−/− and Irf7−/− mice; P. Cresswell (Yale University) for antibody to viperin (anti-viperin); A. Cerny for animal husbandry and genotyping; A. Poltorak for guidance and help with genotyping mice; S. Schattgen for assistance with cell-viability assays; M. Pickering and T. Kowolik for discussions; E. Alnemri and T. Fernandez-Alnemri (Thomas Jefferson University) for discussions and polyclonal antibody to AIM2; and E. Lien for critical reading of the manuscript. Supported by the National Institutes of Health (AI083713 to K.A.F. and E.L.; CA66644 to E.T.S.; AI07349 to S.N.W.; CA034461 to R.W.; and U54 AI-157168 to S.N.V.) and the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (V.A.K.R.).

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Authors and Affiliations

  1. Division of Infectious Diseases and Immunology, Department of Medicine,

    Vijay A K Rathinam, Zhaozhao Jiang, Shruti Sharma, Lisa Waggoner, Brian G Monks, Sandhya Ganesan, Eicke Latz & Katherine A Fitzgerald

  2. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Stephen N Waggoner & Eva Szomolanyi-Tsuda

  3. Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, Maryland, USA

    Leah E Cole & Stefanie N Vogel

  4. Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Sivapriya Kailasan Vanaja

  5. Institute of Clinical Chemistry and Pharmacology, University of Bonn, Germany

    Eicke Latz & Veit Hornung

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  1. Vijay A K Rathinam
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  2. Zhaozhao Jiang
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Contributions

K.A.F. oversaw the entire project; K.A.F., V.A.K.R. and S.N.W. conceived of the research with assistance from S.N.V., E.L. and E.S.-T.; V.A.K.R., B.G.M. and V.H. characterized the gene-trap integration; V.A.K.R. and L.W. did all the genotyping; V.A.K.R., Z.J. and S.N.W. designed and did the experiments with help from S.S., L.W., S.K.V. and S.G.; L.E.C. did the F. tularensis experiments; and K.A.F., V.A.K.R., S.S. and S.N.W. wrote the manuscript.

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Correspondence to Katherine A Fitzgerald.

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Rathinam, V., Jiang, Z., Waggoner, S. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11, 395–402 (2010). https://doi.org/10.1038/ni.1864

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