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

By C. Bauer, P. Duewell, C. Mayer, H. Lehr, Katherine A. Fitzgerald, M. Dauer, J. Tschopp, S. Endres, E. Latz, M. Schnurr. Gut, 2010

868 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/d31be308f5793201258cc1cd3e477ed956dced66

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In Immunology

1. R. Flavell
2. Eran Elinav
3. Shizuo Akira
4. Alexander Y. Rudensky
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In Molecular Biology

1. Jorge Henao-Mejia
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Citations in the corpus

• NLRP6 inflammasome is a regulator of colonic microbial ecology and risk for colitis (2011, neutral): “Upon sensing the relevant signal, they assemble, typically together with the adaptor protein, apoptosis-associated speck-like protein (ASC), into a multiprotein complex that governs cas- pase-1 activation and subsequent cleavage of effector proinflammatory cytokines, including pro-IL-1b and pro-IL-1”
• Inflammasomes in health and disease (2012, background): “Using a common acute and chronic epithelial injury colitis model based on the administration of dextran sulphate to mice, several groups reported decreased disease severity in mice deficient in caspase-1 or NLRP3, which correlated with lower IL-1β production during diseas”