Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation

• Published in: Cell reports (Cambridge) Vol. 19; no. 11; pp. 2319 - 2330
• Main Authors: Błażejewski, Adrian J., Thiemann, Sophie, Schenk, Alexander, Pils, Marina C., Gálvez, Eric J.C., Roy, Urmi, Heise, Ulrike, de Zoete, Marcel R., Flavell, Richard A., Strowig, Till
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.06.2017; Elsevier
• Subjects: Animals; Caspase 1 - metabolism; caspase-1; caspase-11; colitis; colon; DSS; inflammasome; Inflammasomes - metabolism; Inflammation - metabolism; inflammation-induced tumorigenesis; intestine; Intestines - pathology; Mice; Microbiota; microbiota; colitis; intestine; DSS; inflammasome; inflammation-induced tumorigenesis; colon; caspase-11; caspase-1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.05.058

Inflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1−/− and Casp11−/− mice and rederived them into an enhanced barrier facility to standardize the microbiota. We found that caspase-11 does not influence caspase-1-dependent processing of IL-18 in homeostasis and during DSS colitis. Deficiency of caspase-1, but not caspase-11, ameliorated the severity of DSS colitis independent of microbiota composition. Ablation of caspase-1 in intestinal epithelial cells was sufficient to protect mice against DSS colitis. Moreover, Casp1−/− mice developed fewer inflammation-induced intestinal tumors than control mice. These data show that canonical inflammasome activation controls caspase-1 activity, contributing to exacerbation of chemical-induced colitis. [Display omitted] •Microbiota normalization enables the generation of isobiotic mouse lines•Caspase-1, but not caspase-11, exacerbates inflammation during DSS-induced colitis•Caspase-1-driven colitis is independent of the intestinal microbiota composition•Caspase-1 expressed in intestinal epithelial cells exacerbates DSS colitis The discovery of a passenger mutation and colitogenic alterations in the microbiota of Casp1−/−Casp11129mt/129mt mice has called into question the role of caspase-1 in DSS colitis. Błażejewski et al. show using Casp1−/− mice with a standardized gut microbiota that caspase-1, but not caspase-11, exacerbates DSS-induced colitis.