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Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome
  1. Christian Bauer1,
  2. Peter Duewell1,
  3. Christine Mayer1,
  4. Hans Anton Lehr2,
  5. Katherine A Fitzgerald3,
  6. Marc Dauer4,
  7. Jurg Tschopp5,
  8. Stefan Endres6,
  9. Eicke Latz3,
  10. Max Schnurr1
  1. 1Department of Internal Medicine, University of Munich, Munich, Germany
  2. 2Institut Universitaire de Pathologie, Universite de Lausanne, Lausanne, Switzerland
  3. 3Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  4. 4Department of Medicine II, Saarland University Hospital, Homburg/Saar, Germany
  5. 5Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, Epalinges, Switzerland
  6. 6Department of Clinical Pharmacology, University of Munich, Munich, Germany
  1. Correspondence to Dr Max Schnurr, Medizinische Klinik Innenstadt, University of Munich, Ziemssenstr. 1, D-80336 Munich, Germany; Max.Schnurr{at}med.uni-muenchen.de

Abstract

Background The proinflammatory cytokines interleukin 1β (IL-1β) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined.

Methods IL-1β production in response to DSS was studied in macrophages of wild-type, caspase-1−/−, NLRP3−/−, ASC−/−, cathepsin B−/− or cathepsin L−/− mice. Colitis was induced in C57BL/6 and NLRP3−/− mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue.

Results Macrophages incubated with DSS in vitro secreted high levels of IL-1β in a caspase-1-dependent manner. IL-1β secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1β secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3−/− mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency.

Conclusions The NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.

  • Caspase-1
  • DSS
  • IBD
  • IBD models
  • immunoregulation
  • inflammasome
  • molecular immunology
  • NLRP3
  • Revised 18 January 2010
  • Accepted 23 February 2010

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Footnotes

  • CB and PD contributed equally to this work.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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