Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases.
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.
Department of Biochemistry, McGill University, Quebec, Canada.
Jeremy
J
Dupaul-Chicoine
Garabet
G
Yeretssian
Karine
K
Doiron
Kirk S B
KS
Bergstrom
Christian R
CR
McIntire
Philippe M
PM
LeBlanc
Charles
C
Meunier
Claire
C
Turbide
Philippe
P
Gros
Nicole
N
Beauchemin
Bruce A
BA
Vallance
Maya
M
Saleh
D000818:Animals; D020170:Caspase 1 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D053454:Caspase 12 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000150:complications / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis; D007108:Immune Tolerance; D020382:Interleukin-18 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism
D020382:Interleukin-18; D016328:NF-kappa B; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020170:Caspase 1