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

Abstract

Aims: The proinflammatory cytokines 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 multi-protein complex, the NLRP3 inflammasome. Here, we examined the role of the NLRP3 inflammasome in experimental colitis induced by dextran sulfate sodium (DSS). Methods: IL-1β production in response to dextran sulfate sodium (DSS) was studied in macrophages of wild-type (WT), 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 WT mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a comparable level of mucosal protection as NLRP3 deficiency. Conclusions: We identified the NLRP3 inflammasome as a critical check-point of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a novel target for the development of therapeutics for patients with IBD.