Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Carrier Proteins; Caspase 1; Colitis; Dextran Sulfate; Disease Models, Animal; Inflammatory Bowel Diseases; Interleukin-1beta; Lysosomes; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Reactive Oxygen Species; Signal Transduction
Immunology and Infectious Disease
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.
DOI of Published Version
Gut. 2010 Sep;59(9):1192-9. Epub 2010 May 4. Link to article on publisher's site
Bauer C, Duewell P, Mayer C, Lehr H, Fitzgerald KA, Dauer M, Tschopp J, Endres S, Latz E, Schnurr M. (2010). Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Infectious Diseases and Immunology Publications. https://doi.org/10.1136/gut.2009.197822. Retrieved from https://escholarship.umassmed.edu/infdis_pp/56