Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome

  • Gut. 2010 Sep;59(9):1192-9. doi: 10.1136/gut.2009.197822.
Christian Bauer  1 ,  Peter Duewell ,  Christine Mayer ,  Hans Anton Lehr ,  Katherine A Fitzgerald ,  Marc Dauer ,  Jurg Tschopp ,  Stefan Endres ,  Eicke Latz ,  Max Schnurr
Affiliations
  • 1. Medizinische Klinik Innenstadt, University of Munich, Ziemssenstr. 1, D-80336 Munich, Germany.
PMID: 20442201 DOI: 10.1136/gut.2009.197822
Abstract

Background: The proinflammatory cytokines interleukin 1beta (IL-1beta) 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-1beta 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-1beta in a caspase-1-dependent manner. IL-1beta secretion was abrogated in Macrophages lacking NLRP3, ASC or Caspase-1, indicating that DSS activates Caspase-1 via the NLRP3 inflammasome. Moreover, IL-1beta 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.