title: Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome.
abstract: 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.
authors.affiliation: Medizinische Klinik Innenstadt, University of Munich, Ziemssenstr. 1, D-80336 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bauer
authors.forename: Peter
authors.initials: P
authors.lastname: Duewell
authors.forename: Christine
authors.initials: C
authors.lastname: Mayer
authors.forename: Hans Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Marc
authors.initials: M
authors.lastname: Dauer
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Max
authors.initials: M
authors.lastname: Schnurr
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D008247:Lysosomes / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D016264:Dextran Sulfate; D020170:Caspase 1