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.
Dupaul-Chicoine
Jeremy
J
Department of Biochemistry, McGill University, Quebec, Canada.
Yeretssian
Garabet
G
Doiron
Karine
K
Bergstrom
Kirk S B
KS
McIntire
Christian R
CR
LeBlanc
Philippe M
PM
Meunier
Charles
C
Turbide
Claire
C
Gros
Philippe
P
Beauchemin
Nicole
N
Vallance
Bruce A
BA
Saleh
Maya
M
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