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

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