Home LiteratureArticle Details
PMID: 20351693 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

The AIM2 inflammasome is critical for innate immunity to Francisella tularensis.

Nature immunology ·Vol. 11 ·No. 5 ·2010-05-00 ·Pages 385-93

Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S, Wu J, Datta P, McCormick M, Huang L, McDermott E, Eisenlohr L, Landel CP, Alnemri ES

Abstract

Francisella tularensis, the causative agent of tularemia, infects host macrophages, which triggers production of the proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18. We elucidate here how host macrophages recognize F. tularensis and elicit this proinflammatory response. Using mice deficient in the DNA-sensing inflammasome component AIM2, we demonstrate here that AIM2 is required for sensing F. tularensis. AIM2-deficient mice were extremely susceptible to F. tularensis infection, with greater mortality and bacterial burden than that of wild-type mice. Caspase-1 activation, IL-1beta secretion and cell death were absent in Aim2(-/-) macrophages in response to F. tularensis infection or the presence of cytoplasmic DNA. Our study identifies AIM2 as a crucial sensor of F. tularensis infection and provides genetic proof of its critical role in host innate immunity to intracellular pathogens.

MeSH Terms
Animals Calcium Signaling/immunology Caspase 1/genetics,immunology,metabolism Cells, Cultured DNA-Binding Proteins Francisella tularensis/immunology,pathogenicity Humans Immunity, Innate Interferon Regulatory Factor-3/genetics,immunology,metabolism Interferon Type I/immunology Interleukin-1beta/biosynthesis,genetics,immunology L-Lactate Dehydrogenase/genetics,immunology,metabolism Macrophages/immunology,metabolism,pathology Mice Mice, Knockout Multiprotein Complexes/genetics,immunology,metabolism Nuclear Proteins/genetics,immunology,metabolism Protein Multimerization Tularemia/genetics,immunology,metabolism
Chemicals
Aim2 protein, mouse DNA-Binding Proteins Interferon Regulatory Factor-3 Interferon Type I Interleukin-1beta Irf3 protein, mouse Multiprotein Complexes Nuclear Proteins L-Lactate Dehydrogenase Caspase 1
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Fernandes-Alnemri Teresa
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Yu Je-Wook
Juliana Christine
Solorzano Leobaldo
Kang Seokwon
Wu Jianghong
Datta Pinaki
McCormick Margaret
Huang Lan
McDermott Erin
Eisenlohr Laurence
Landel Carlisle P
Alnemri Emad S
References (45)
45 references, click to expand
  1. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants.
    Mol Cell. 2007 Oct 26;28(2):214-27 PMID: 17964261
  2. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization.
    Nat Immunol. 2008 Aug;9(8):847-56 PMID: 18604214
  3. Virulent and avirulent strains of Francisella tularensis prevent acidification and maturation of their phagosomes and escape into the cytoplasm in human macrophages.
    Infect Immun. 2004 Jun;72(6):3204-17 PMID: 15155622
  4. Autophagy-mediated reentry of Francisella tularensis into the endocytic compartment after cytoplasmic replication.
    Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14578-83 PMID: 16983090
  5. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis.
    Mol Cell. 2003 Mar;11(3):591-604 PMID: 12667444
  6. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.
    J Biol Chem. 2002 Jun 14;277(24):21119-22 PMID: 11967258
  7. International Gene Trap Project: towards gene-driven saturation mutagenesis in mice.
    Curr Pharm Biotechnol. 2009 Feb;10(2):221-9 PMID: 19199955
  8. Life on the inside: the intracellular lifestyle of cytosolic bacteria.
    Nat Rev Microbiol. 2009 May;7(5):333-40 PMID: 19369949
  9. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA.
    Science. 2009 Feb 20;323(5917):1057-60 PMID: 19131592
  10. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf.
    Nat Immunol. 2006 Jun;7(6):569-75 PMID: 16648853
  11. Phagocytosis-induced apoptosis of macrophages is linked to uptake, killing and degradation of bacteria.
    Eur J Immunol. 2008 Jan;38(1):204-15 PMID: 18085665
  12. 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
  13. Francisella tularensis phagosomal escape does not require acidification of the phagosome.
    Infect Immun. 2009 May;77(5):1757-73 PMID: 19237528
  14. Bactericidal activity of alveolar macrophages is suppressed by V-ATPase inhibition.
    Lung. 2000;178(2):91-104 PMID: 10773135
  15. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA.
    Nature. 2009 Mar 26;458(7237):509-13 PMID: 19158676
  16. 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
  17. The inflammasomes: guardians of the body.
    Annu Rev Immunol. 2009;27:229-65 PMID: 19302040
  18. Pathogen recognition in the innate immune response.
    Biochem J. 2009 Apr 28;420(1):1-16 PMID: 19382893
  19. Cryopyrin activates the inflammasome in response to toxins and ATP.
    Nature. 2006 Mar 9;440(7081):228-32 PMID: 16407890
  20. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production.
    Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9982-7 PMID: 16785446
  21. Assembly, purification, and assay of the activity of the ASC pyroptosome.
    Methods Enzymol. 2008;442:251-70 PMID: 18662574
  22. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta.
    Nat Immunol. 2008 Aug;9(8):857-65 PMID: 18604209
  23. The early phagosomal stage of Francisella tularensis determines optimal phagosomal escape and Francisella pathogenicity island protein expression.
    Infect Immun. 2008 Dec;76(12):5488-99 PMID: 18852245
  24. Toll-like receptor 2 is required for inflammatory responses to Francisella tularensis LVS.
    Infect Immun. 2006 May;74(5):2809-16 PMID: 16622218
  25. The Francisella tularensis pathogenicity island protein IglC and its regulator MglA are essential for modulating phagosome biogenesis and subsequent bacterial escape into the cytoplasm.
    Cell Microbiol. 2005 Jul;7(7):969-79 PMID: 15953029
  26. 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
  27. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
    Nature. 2004 Jul 8;430(6996):213-8 PMID: 15190255
  28. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC.
    Nature. 2009 Mar 26;458(7237):514-8 PMID: 19158675
  29. Pathogen recognition and innate immunity.
    Cell. 2006 Feb 24;124(4):783-801 PMID: 16497588
  30. TLR-dependent control of Francisella tularensis infection and host inflammatory responses.
    PLoS One. 2009 Nov 20;4(11):e7920 PMID: 19936231
  31. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin.
    Nat Genet. 2006 Feb;38(2):240-4 PMID: 16429160
  32. Toll-like receptor 2 is required for control of pulmonary infection with Francisella tularensis.
    Infect Immun. 2006 Jun;74(6):3657-62 PMID: 16714598
  33. 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
  34. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
    J Immunol. 2009 Jul 15;183(2):787-91 PMID: 19570822
  35. Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome.
    J Biol Chem. 2010 Mar 26;285(13):9792-9802 PMID: 20093358
  36. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response.
    Nature. 2008 Mar 6;452(7183):103-7 PMID: 18288107
  37. Acquisition of the vacuolar ATPase proton pump and phagosome acidification are essential for escape of Francisella tularensis into the macrophage cytosol.
    Infect Immun. 2008 Jun;76(6):2671-7 PMID: 18390995
  38. A public gene trap resource for mouse functional genomics.
    Nat Genet. 2004 Jun;36(6):543-4 PMID: 15167922
  39. Pyrin critical to macrophage IL-1beta response to Francisella challenge.
    J Immunol. 2009 Jun 15;182(12):7982-9 PMID: 19494323
  40. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages.
    Nat Immunol. 2006 Jun;7(6):576-82 PMID: 16648852
  41. 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
  42. The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing.
    Cell Death Differ. 2007 Aug;14(8):1457-66 PMID: 17431422
  43. NLR-mediated control of inflammasome assembly in the host response against bacterial pathogens.
    Semin Immunol. 2009 Aug;21(4):199-207 PMID: 19539499
  44. Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization.
    Cell Death Differ. 2006 Feb;13(2):236-49 PMID: 16037825
  45. The NLR gene family: a standard nomenclature.
    Immunity. 2008 Mar;28(3):285-7 PMID: 18341998
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1859
Published
2010-05-00
Epub
2010-00-28
Pages
385-93
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC3111085
Subset
IM
Grants
NIAMS NIH HHS · R01 AR055398-13 · United States
NCI NIH HHS · T32-CA09678 · United States
NIAMS NIH HHS · AR055398 · United States
NCI NIH HHS · T32 CA009678 · United States
NIA NIH HHS · R01 AG014357 · United States
NIA NIH HHS · AG14357 · United States
NIAMS NIH HHS · R01 AR055398 · United States
NIA NIH HHS · R01 AG014357-13 · United States
Corrections
CommentIn
PMID: 20404848
CommentIn
PMID: 20425914
External Links
PubMed source DOI: 10.1038/ni.1859 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2