title: Caspase-11 attenuates gastrointestinal inflammation and experimental colitis pathogenesis.
abstract: Nucleotide-binding domain and leucine-rich repeat containing protein inflammasome formation plays an essential role in modulating immune system homeostasis in the gut. Recently, a caspase-11 noncanonical inflammasome has been characterized and appears to modulate many biological functions that were previously considered to be solely dependent on caspase-1 and the canonical inflammasome. To better elucidate the function of this noncanonical inflammasome during inflammatory bowel disease, experimental colitis was induced in wild-type and Casp11(-/-) mice utilizing dextran sulfate sodium (DSS). Here, we report that caspase-11 attenuates acute experimental colitis pathogenesis. Casp11(-/-) mice showed significantly increased morbidity and colon inflammation following DSS exposure. Subsequent cytokine analysis revealed that IL-1β and IL-18 levels in the colon were significantly reduced in the Casp11(-/-) mice compared with the wild-type animals. Additional mechanistic studies utilizing IL-1β and IL-18 reconstitution revealed that Casp11(-/-) hypersensitivity was associated with the loss of both of these cytokines. Bone marrow reconstitution experiments further revealed that caspase-11 gene expression and function in both hematopoietic- and nonhematopoietic-derived cells contribute to disease attenuation. Interestingly, unlike caspase-1, caspase-11 does not appear to influence relapsing remitting disease progression or the development of colitis-associated tumorigenesis. Together, these data identify caspase-11 as a critical factor protecting the host during acute DSS-induced colonic injury and inflammation but not during chronic inflammation and tumorigenesis.
authors.affiliation: Virginia Tech, Virginia Maryland Regional College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia.
authors.forename: Tere M
authors.initials: TM
authors.lastname: Williams
authors.affiliation: Virginia Tech, Virginia Maryland Regional College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Leeth
authors.affiliation: Virginia Tech, Virginia Maryland Regional College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Rothschild
authors.affiliation: Virginia Tech, Virginia Maryland Regional College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia.
authors.forename: Dylan K
authors.initials: DK
authors.lastname: McDaniel
authors.affiliation: Virginia Tech, Virginia Maryland Regional College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia.
authors.forename: Sheryl L
authors.initials: SL
authors.lastname: Coutermarsh-Ott
authors.affiliation: Virginia Tech, Virginia Maryland Regional College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia.
authors.forename: Alysha E
authors.initials: AE
authors.lastname: Simmons
authors.affiliation: Virginia Tech, Virginia Maryland Regional College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia.
authors.forename: Kye H
authors.initials: KH
authors.lastname: Kable
authors.affiliation: Virginia Tech, Virginia Maryland Regional College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia.
authors.forename: Bettina
authors.initials: B
authors.lastname: Heid
authors.affiliation: Virginia Tech, Virginia Maryland Regional College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia icallen@vt.edu.
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D020169:Caspases / Q000235:genetics*; D053471:Caspases, Initiator; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D041981:Gastrointestinal Tract / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis / Q000235:genetics; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D016264:Dextran Sulfate; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1
keywords: colitis-associated cancer; inflammasome; inflammatory bowel disease; noncanonical inflammasome; nucleotide-binding domain and leucine-rich repeat containing protein