TY - JOUR
T1 - Control of Intestinal Homeostasis, Colitis, and Colitis-Associated Colorectal Cancer by the Inflammatory Caspases
AU - Dupaul-Chicoine, Jeremy
AU - Yeretssian, Garabet
AU - Doiron, Karine
AU - Bergstrom, Kirk S.B.
AU - McIntire, Christian R.
AU - LeBlanc, Philippe M.
AU - Meunier, Charles
AU - Turbide, Claire
AU - Gros, Philippe
AU - Beauchemin, Nicole
AU - Vallance, Bruce A.
AU - Saleh, Maya
N1 - Funding Information:
This work was supported by grants from the Canadian Institute of Health Research to N.B., (MOP68984), to B.V., (MOP82801), and to M.S. and the Burroughs Wellcome Foundation to M.S. B.V. is the CHILD Foundation Research Scholar and a Canada Research Chair (Tier 2), and M.S. is a CIHR New Investigator. J.D.C. was supported by a Canadian Society for Immunology summer studentship and a McGill University Health Centre graduate studentship. We thank R. Flavell and V. Dixit for providing Casp1 −/− and Asc −/− mice breeder pairs. We also thank P. D'Arcy and M.-L. Goulet for technical assistance and the McGill University and Génome Québec Innovation Centre for hybridization of the microarray.
PY - 2010/3
Y1 - 2010/3
N2 - Inflammatory caspases are essential effectors of inflammation and cell death. Here, we investigated their roles in colitis and colorectal cancer and report a bimodal regulation of intestinal homeostasis, inflammation and tumorigenesis by caspases-1 and -12. Casp1-/- mice exhibited defects in mucosal tissue repair and succumbed rapidly after dextran sulfate sodium administration. This phenotype was rescued by administration of exogenous interleukin-18 and was partially reproduced in mice deficient in the inflammasome adaptor ASC. Casp12-/- mice, in which the inflammasome is derepressed, were resistant to acute colitis and showed signs of enhanced repair. Together with their increased inflammatory response, the enhanced repair response of Casp12-/- mice rendered them more susceptible to colorectal cancer induced by azoxymethane (AOM)+DSS. Taken together, our results indicate that the inflammatory caspases are critical in the induction of inflammation in the gut after injury, which is necessary for tissue repair and maintenance of immune tolerance.
AB - Inflammatory caspases are essential effectors of inflammation and cell death. Here, we investigated their roles in colitis and colorectal cancer and report a bimodal regulation of intestinal homeostasis, inflammation and tumorigenesis by caspases-1 and -12. Casp1-/- mice exhibited defects in mucosal tissue repair and succumbed rapidly after dextran sulfate sodium administration. This phenotype was rescued by administration of exogenous interleukin-18 and was partially reproduced in mice deficient in the inflammasome adaptor ASC. Casp12-/- mice, in which the inflammasome is derepressed, were resistant to acute colitis and showed signs of enhanced repair. Together with their increased inflammatory response, the enhanced repair response of Casp12-/- mice rendered them more susceptible to colorectal cancer induced by azoxymethane (AOM)+DSS. Taken together, our results indicate that the inflammatory caspases are critical in the induction of inflammation in the gut after injury, which is necessary for tissue repair and maintenance of immune tolerance.
KW - Cellimmuno
KW - Molimmuno
UR - http://www.scopus.com/inward/record.url?scp=77949965210&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2010.02.012
DO - 10.1016/j.immuni.2010.02.012
M3 - Article
C2 - 20226691
AN - SCOPUS:77949965210
SN - 1074-7613
VL - 32
SP - 367
EP - 378
JO - Immunity
JF - Immunity
IS - 3
ER -