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PMID: 20351692 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature immunology ·Vol. 11 ·No. 5 ·2010-05-00 ·Pages 395-402

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

Abstract

Inflammasomes regulate the activity of caspase-1 and the maturation of interleukin 1beta (IL-1beta) 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-1beta 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-gamma, 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.

MeSH Terms
Animals Apoptosis Regulatory Proteins CARD Signaling Adaptor Proteins Caspase 1/genetics,immunology,metabolism Cell Line Cytokines/genetics,immunology,metabolism Cytoskeletal Proteins/genetics DNA/immunology DNA Virus Infections/genetics,immunology,metabolism DNA Viruses/growth & development,immunology,pathogenicity DNA-Binding Proteins Francisella tularensis/immunology,pathogenicity Humans Immunity, Innate Killer Cells, Natural/immunology,metabolism,microbiology,pathology,virology Listeriosis/genetics,immunology,metabolism Lymphocyte Activation/genetics Macrophages/immunology,metabolism,microbiology,pathology,virology Mice Mice, Inbred C57BL Mice, Knockout Multiprotein Complexes/genetics,immunology,metabolism Nuclear Proteins/genetics,immunology,metabolism Signal Transduction/genetics,immunology Transcription Factors/genetics,immunology,metabolism Tularemia/genetics,immunology,metabolism Viral Load/genetics,immunology
Chemicals
Aim2 protein, mouse Apoptosis Regulatory Proteins CARD Signaling Adaptor Proteins Cytokines Cytoskeletal Proteins DNA-Binding Proteins Multiprotein Complexes Nuclear Proteins Pycard protein, mouse Transcription Factors DNA Caspase 1
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Rathinam Vijay A K
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA .
Jiang Zhaozhao
Waggoner Stephen N
Sharma Shruti
Cole Leah E
Waggoner Lisa
Vanaja Sivapriya Kailasan
Monks Brian G
Ganesan Sandhya
Latz Eicke
Hornung Veit
Vogel Stefanie N
Szomolanyi-Tsuda Eva
Fitzgerald Katherine A
References (53)
53 references, click to expand
  1. A soluble receptor for interleukin-1 beta encoded by vaccinia virus: a novel mechanism of virus modulation of the host response to infection.
    Cell. 1992 Oct 2;71(1):153-67 PMID: 1394428
  2. The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis.
    J Exp Med. 2007 Jul 9;204(7):1559-69 PMID: 17562815
  3. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice.
    J Immunol. 1997 Sep 1;159(5):2452-61 PMID: 9278338
  4. Toll-like receptors in innate immunity.
    Int Immunol. 2005 Jan;17(1):1-14 PMID: 15585605
  5. Activation of the inflammasome upon Francisella tularensis infection: interplay of innate immune pathways and virulence factors.
    Cell Microbiol. 2007 Nov;9(11):2543-51 PMID: 17662071
  6. Innate immune response to Francisella tularensis is mediated by TLR2 and caspase-1 activation.
    J Leukoc Biol. 2006 Oct;80(4):766-73 PMID: 16895974
  7. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria.
    J Biol Chem. 2007 Jun 29;282(26):18810-8 PMID: 17491021
  8. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection.
    J Immunol. 2008 Jun 1;180(11):7558-64 PMID: 18490757
  9. Introduction of Francisella tularensis at skin sites induces resistance to infection and generation of protective immunity.
    Microb Pathog. 1992 Nov;13(5):417-21 PMID: 1297917
  10. The fungal pattern recognition receptor, Dectin-1, and the associated cluster of C-type lectin-like receptors.
    FEMS Microbiol Lett. 2009 Jan;290(2):121-8 PMID: 19025564
  11. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA.
    Nature. 2009 Mar 26;458(7237):509-13 PMID: 19158676
  12. Toll-like receptor and RIG-I-like receptor signaling.
    Ann N Y Acad Sci. 2008 Nov;1143:1-20 PMID: 19076341
  13. Type I interferon signaling is required for activation of the inflammasome during Francisella infection.
    J Exp Med. 2007 May 14;204(5):987-94 PMID: 17452523
  14. The inflammasomes: guardians of the body.
    Annu Rev Immunol. 2009;27:229-65 PMID: 19302040
  15. Macrophage proinflammatory response to Francisella tularensis live vaccine strain requires coordination of multiple signaling pathways.
    J Immunol. 2008 May 15;180(10):6885-91 PMID: 18453609
  16. Vital involvement of a natural killer cell activation receptor in resistance to viral infection.
    Science. 2001 May 4;292(5518):934-7 PMID: 11340207
  17. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H.
    J Exp Med. 2001 Jul 2;194(1):29-44 PMID: 11435470
  18. Cryopyrin activates the inflammasome in response to toxins and ATP.
    Nature. 2006 Mar 9;440(7081):228-32 PMID: 16407890
  19. Biologic basis for interleukin-1 in disease.
    Blood. 1996 Mar 15;87(6):2095-147 PMID: 8630372
  20. The Ifi 200 genes: an emerging family of IFN-inducible genes.
    Biochimie. 1998 Aug-Sep;80(8-9):721-8 PMID: 9865494
  21. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response.
    Nature. 2007 Jul 26;448(7152):501-5 PMID: 17618271
  22. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation.
    Cell Death Differ. 2007 Sep;14(9):1590-604 PMID: 17599095
  23. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production.
    Nat Immunol. 2010 Jan;11(1):63-9 PMID: 19915568
  24. Intracellular DNA recognition.
    Nat Rev Immunol. 2010 Feb;10(2):123-30 PMID: 20098460
  25. Compartmental differences in NK cell responsiveness to IL-12 during lymphocytic choriomeningitis virus infection.
    J Immunol. 2000 Jan 15;164(2):994-1001 PMID: 10623849
  26. Genetic mapping of Cmv1 in the region of mouse chromosome 6 encoding the NK gene complex-associated loci Ly49 and musNKR-P1.
    Genomics. 1995 Jun 10;27(3):435-41 PMID: 7558024
  27. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome.
    Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3076-80 PMID: 20133635
  28. RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity.
    Cytokine Growth Factor Rev. 2007 Oct-Dec;18(5-6):545-51 PMID: 17683970
  29. Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1beta, depending on listeriolysin O and NLRP3.
    J Immunol. 2010 Jan 15;184(2):922-30 PMID: 20008285
  30. Two vaccinia virus proteins structurally related to the interleukin-1 receptor and the immunoglobulin superfamily.
    J Gen Virol. 1991 Mar;72 ( Pt 3):511-8 PMID: 1826022
  31. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC.
    Nature. 2009 Mar 26;458(7237):514-8 PMID: 19158675
  32. Toll-like receptor 2-mediated signaling requirements for Francisella tularensis live vaccine strain infection of murine macrophages.
    Infect Immun. 2007 Aug;75(8):4127-37 PMID: 17517865
  33. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin.
    Nat Genet. 2006 Feb;38(2):240-4 PMID: 16429160
  34. Interleukin 18 and interleukin 18 binding protein: possible role in immunosuppression of chronic renal failure.
    Blood Purif. 2003;21(3):258-70 PMID: 12784053
  35. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
    Nature. 2009 Oct 8;461(7265):788-92 PMID: 19776740
  36. Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis.
    J Exp Med. 2005 Oct 17;202(8):1043-9 PMID: 16230474
  37. Inflammasome recognition of influenza virus is essential for adaptive immune responses.
    J Exp Med. 2009 Jan 16;206(1):79-87 PMID: 19139171
  38. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily.
    Nat Genet. 2001 May;28(1):42-5 PMID: 11326273
  39. The HIN-200 family: more than interferon-inducible genes?
    Exp Cell Res. 2005 Aug 1;308(1):1-17 PMID: 15896773
  40. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA.
    Science. 2009 Feb 20;323(5917):1057-60 PMID: 19131592
  41. Innate and adaptive immunity to Francisella.
    Ann N Y Acad Sci. 2007 Jun;1105:284-324 PMID: 17468235
  42. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate.
    Nat Immunol. 2009 Oct;10(10):1065-72 PMID: 19609254
  43. Dendritic cells from C57BL/6 mice undergo activation and induce Th1-effector cell responses against Campylobacter jejuni.
    Microbes Infect. 2008 Oct;10(12-13):1316-24 PMID: 18725315
  44. Inflammasomes: guardians of cytosolic sanctity.
    Immunol Rev. 2009 Jan;227(1):95-105 PMID: 19120479
  45. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling.
    Immunity. 2007 Apr;26(4):433-43 PMID: 17433728
  46. A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection.
    Immunity. 2005 Dec;23(6):587-98 PMID: 16356857
  47. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome.
    Nat Immunol. 2009 Mar;10(3):266-72 PMID: 19158679
  48. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway.
    Cell. 2009 Aug 7;138(3):576-91 PMID: 19631370
  49. The inflammasomes: mechanisms of activation and function.
    Curr Opin Immunol. 2010 Feb;22(1):28-33 PMID: 20060699
  50. Immunological and inflammatory functions of the interleukin-1 family.
    Annu Rev Immunol. 2009;27:519-50 PMID: 19302047
  51. Aberrant DAP12 signaling in the 129 strain of mice: implications for the analysis of gene-targeted mice.
    J Immunol. 2002 Aug 15;169(4):1721-8 PMID: 12165492
  52. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.
    Nat Immunol. 2003 May;4(5):491-6 PMID: 12692549
  53. Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice.
    J Virol. 1984 Oct;52(1):119-28 PMID: 6207307
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1864
Published
2010-05-00
Epub
2010-00-28
Pages
395-402
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC2887480
Subset
IM
Grants
NIAID NIH HHS · U54 AI-157168 · United States
NCI NIH HHS · CA66644 · United States
NIAID NIH HHS · AI07349 · United States
NIAID NIH HHS · R01 AI083713-01 · United States
NIAID NIH HHS · T32 AI007349 · United States
NCI NIH HHS · CA034461 · United States
NIAID NIH HHS · R01 AI083713 · United States
NIAID NIH HHS · AI083713 · United States
NCI NIH HHS · R01 CA034461 · United States
NCI NIH HHS · R01 CA066644 · United States
Corrections
CommentIn
PMID: 20404848
External Links
PubMed source DOI: 10.1038/ni.1864 PMC Full Text View journal details
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