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

Publication date: 13 June 2017
Source:Cell Reports, Volume 19, Issue 11
Author(s): Adrian J. Błażejewski, Sophie Thiemann, Alexander Schenk, Marina C. Pils, Eric J.C. Gálvez, Urmi Roy, Ulrike Heise, Marcel R. de Zoete, Richard A. Flavell, Till Strowig
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.

Graphical abstract

Teaser

The discovery of a passenger mutation and colitogenic alterations in the microbiota of Casp1^−/−Casp11^129mt/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.


http://ift.tt/2t2uo0q