Journal Article

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

Bauer, Christian, Tschopp, Jurg, Duewell, Peter, Schnurr, Max, Lehr, Hans Anton, Fitzgerald, Katherine A, Dauer, Marc, Mayer, Christine, Endres, Stefan, Latz, Eicke

2010

Overview

BackgroundThe 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.MethodsIL-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.ResultsMacrophages 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.ConclusionsThe 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group,BMJ Publishing Group LTD
• Subject: Animals / Biological and medical sciences / Carrier Proteins - physiology / Caspase 1 - physiology / Caspase-1 / Cathepsin B / Cathepsin L / Colitis / Colitis - chemically induced / Colitis - metabolism / Colitis - physiopathology / Dextran / Dextran Sulfate / Disease Models, Animal / Drug development / DSS / Gastroenterology. Liver. Pancreas. Abdomen / Genes / IBD / IBD models / IL-1β / immunoregulation / inflammasome / Inflammasomes / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - metabolism / Inflammatory Bowel Diseases - physiopathology / Interleukin-1beta - metabolism / Lysosomes - physiology / Macrophages / Macrophages - metabolism / Medical sciences / Mice / Mice, Inbred C57BL / Mice, Knockout / molecular immunology / Mutation / NLR Family, Pyrin Domain-Containing 3 Protein / NLRP3 / Oral administration / Phagocytosis / Reactive oxygen species / Reactive Oxygen Species - metabolism / Rodents / Signal Transduction - physiology / Sodium sulfate / Studies