Home LiteratureArticle Details
PMID: 20603313 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella.

The Journal of experimental medicine ·Vol. 207 ·No. 8 ·2010-08-02 ·Pages 1745-55

Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit VM, Monack DM

Abstract

Intracellular pathogens and endogenous danger signals in the cytosol engage NOD-like receptors (NLRs), which assemble inflammasome complexes to activate caspase-1 and promote the release of proinflammatory cytokines IL-1beta and IL-18. However, the NLRs that respond to microbial pathogens in vivo are poorly defined. We show that the NLRs NLRP3 and NLRC4 both activate caspase-1 in response to Salmonella typhimurium. Responding to distinct bacterial triggers, NLRP3 and NLRC4 recruited ASC and caspase-1 into a single cytoplasmic focus, which served as the site of pro-IL-1beta processing. Consistent with an important role for both NLRP3 and NLRC4 in innate immune defense against S. typhimurium, mice lacking both NLRs were markedly more susceptible to infection. These results reveal unexpected redundancy among NLRs in host defense against intracellular pathogens in vivo.

MeSH Terms
Animal Structures/microbiology Animals Apoptosis Regulatory Proteins/genetics Bacterial Proteins/genetics Blood/microbiology CARD Signaling Adaptor Proteins Calcium-Binding Proteins/genetics Carrier Proteins/genetics Caspase 1/genetics,metabolism Caspase Inhibitors Cysteine Proteinase Inhibitors/pharmacology Cytoplasmic Structures/drug effects,genetics,immunology,metabolism Cytoskeletal Proteins/genetics,metabolism Flagellin/genetics Immunity, Innate/physiology Interleukin-1/metabolism Interleukin-18/blood,metabolism Interleukin-1beta/blood,metabolism Macrophages/metabolism,microbiology Membrane Proteins/genetics Mice Mice, Inbred Strains Mice, Knockout Models, Immunological NLR Family, Pyrin Domain-Containing 3 Protein Protein Precursors/metabolism Protein Transport/genetics,immunology Salmonella Infections/immunology,microbiology Salmonella typhimurium/genetics,immunology
Chemicals
Apoptosis Regulatory Proteins Bacterial Proteins CARD Signaling Adaptor Proteins Calcium-Binding Proteins Carrier Proteins Caspase Inhibitors Cysteine Proteinase Inhibitors Cytoskeletal Proteins Interleukin-1 Interleukin-18 Interleukin-1beta Ipaf protein, mouse Membrane Proteins NLR Family, Pyrin Domain-Containing 3 Protein Nlrp3 protein, mouse Protein Precursors Pycard protein, mouse SPI-2 protein, Salmonella Spi1 protein, Salmonella interleukin 1 precursor Flagellin Caspase 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Broz Petr
Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
Newton Kim
Lamkanfi Mohamed
Mariathasan Sanjeev
Dixit Vishva M
Monack Denise M
References (47)
47 references, click to expand
  1. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection.
    J Immunol. 2008 Jun 1;180(11):7558-64 PMID: 18490757
  2. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA.
    Immunity. 2009 Apr 17;30(4):556-65 PMID: 19362020
  3. Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1.
    J Biol Chem. 2001 Jul 27;276(30):28309-13 PMID: 11390368
  4. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages.
    PLoS Pathog. 2007 Aug 10;3(8):e111 PMID: 17696608
  5. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC.
    Nature. 2009 Mar 26;458(7237):514-8 PMID: 19158675
  6. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.
    Immunity. 2009 Apr 17;30(4):566-75 PMID: 19362023
  7. Salmonella pathogenicity island 2-dependent macrophage death is mediated in part by the host cysteine protease caspase-1.
    Cell Microbiol. 2001 Dec;3(12):825-37 PMID: 11736994
  8. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.
    J Biol Chem. 2006 Dec 1;281(48):36560-8 PMID: 17008311
  9. 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
  10. Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome.
    J Immunol. 2009 Sep 15;183(6):3578-81 PMID: 19684085
  11. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms.
    Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4312-7 PMID: 18337499
  12. Growth phase-regulated induction of Salmonella-induced macrophage apoptosis correlates with transient expression of SPI-1 genes.
    J Bacteriol. 1999 Jun;181(11):3433-7 PMID: 10348855
  13. NLR-mediated control of inflammasome assembly in the host response against bacterial pathogens.
    Semin Immunol. 2009 Aug;21(4):199-207 PMID: 19539499
  14. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.
    Nature. 2009 May 21;459(7245):433-6 PMID: 19339971
  15. Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome.
    J Immunol. 2009 May 15;182(10):6460-9 PMID: 19414800
  16. Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf.
    J Biol Chem. 2006 Nov 17;281(46):35217-23 PMID: 16984919
  17. In vivo, fliC expression by Salmonella enterica serovar Typhimurium is heterogeneous, regulated by ClpX, and anatomically restricted.
    Mol Microbiol. 2006 Aug;61(3):795-809 PMID: 16803592
  18. ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection.
    Cell Microbiol. 2008 Sep;10(9):1866-78 PMID: 18503637
  19. Mechanisms of interleukin-1beta release.
    Immunobiology. 2009;214(7):543-53 PMID: 19250700
  20. Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis.
    J Exp Med. 2006 Jun 12;203(6):1407-12 PMID: 16717117
  21. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis.
    J Biol Chem. 2001 Oct 19;276(42):39320-9 PMID: 11498534
  22. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA.
    Nature. 2009 Mar 26;458(7237):509-13 PMID: 19158676
  23. The inflammasomes: guardians of the body.
    Annu Rev Immunol. 2009;27:229-65 PMID: 19302040
  24. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide.
    Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7803-8 PMID: 18511561
  25. 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
  26. Salmonella maintains the integrity of its intracellular vacuole through the action of SifA.
    EMBO J. 2000 Jul 3;19(13):3235-49 PMID: 10880437
  27. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases.
    PLoS Pathog. 2009 Aug;5(8):e1000559 PMID: 19696895
  28. Malarial hemozoin is a Nalp3 inflammasome activating danger signal.
    PLoS One. 2009 Aug 04;4(8):e6510 PMID: 19652710
  29. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation.
    Mol Cell. 2007 Mar 9;25(5):713-24 PMID: 17349957
  30. Cryopyrin activates the inflammasome in response to toxins and ATP.
    Nature. 2006 Mar 9;440(7081):228-32 PMID: 16407890
  31. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation.
    Nat Rev Immunol. 2007 Jan;7(1):31-40 PMID: 17186029
  32. 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
  33. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
    Nature. 2004 Jul 8;430(6996):213-8 PMID: 15190255
  34. An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans.
    Cell Host Microbe. 2009 May 8;5(5):487-97 PMID: 19454352
  35. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome.
    J Exp Med. 2007 Dec 24;204(13):3235-45 PMID: 18070936
  36. Contribution of flagellin pattern recognition to intestinal inflammation during Salmonella enterica serotype typhimurium infection.
    Infect Immun. 2009 May;77(5):1904-16 PMID: 19237529
  37. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome.
    Curr Biol. 2004 Nov 9;14(21):1929-34 PMID: 15530394
  38. Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain.
    J Immunol. 2009 Mar 1;182(5):3173-82 PMID: 19234215
  39. Kinetic properties of ASC protein aggregation in epithelial cells.
    J Cell Physiol. 2010 Mar;222(3):738-47 PMID: 20020448
  40. Active caspase-1 is a regulator of unconventional protein secretion.
    Cell. 2008 Mar 7;132(5):818-31 PMID: 18329368
  41. Caspase-1-mediated activation of interleukin-1beta (IL-1beta) and IL-18 contributes to innate immune defenses against Salmonella enterica serovar Typhimurium infection.
    Infect Immun. 2006 Aug;74(8):4922-6 PMID: 16861683
  42. Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity.
    PLoS Pathog. 2006 Mar;2(3):e18 PMID: 16552444
  43. 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
  44. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf.
    Nat Immunol. 2006 Jun;7(6):569-75 PMID: 16648853
  45. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells.
    J Biol Chem. 1999 Nov 26;274(48):33835-8 PMID: 10567338
  46. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response.
    Nature. 2008 Mar 6;452(7183):103-7 PMID: 18288107
  47. Asc and Ipaf Inflammasomes direct distinct pathways for caspase-1 activation in response to Legionella pneumophila.
    Infect Immun. 2009 May;77(5):1981-91 PMID: 19237518
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20100257
Published
2010-08-02
Epub
2010-00-05
Pages
1745-55
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2916133
Subset
IM
Grants
NIAID NIH HHS · P01 AI063302 · United States
External Links
PubMed source DOI: 10.1084/jem.20100257 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