title: Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens.
abstract: Inflammasome-mediated host defenses have been extensively studied in innate immune cells. Whether inflammasomes function for innate defense in intestinal epithelial cells, which represent the first line of defense against enteric pathogens, remains unknown. We observed enhanced Salmonella enterica serovar Typhimurium colonization in the intestinal epithelium of caspase-11-deficient mice, but not at systemic sites. In polarized epithelial monolayers, siRNA-mediated depletion of caspase-4, a human ortholog of caspase-11, also led to increased bacterial colonization. Decreased rates of pyroptotic cell death, a host defense mechanism that extrudes S. Typhimurium-infected cells from the polarized epithelium, accounted for increased pathogen burdens. The caspase-4 inflammasome also governs activation of the proinflammatory cytokine, interleukin (IL)-18, in response to intracellular (S. Typhimurium) and extracellular (enteropathogenic Escherichia coli) enteric pathogens, via intracellular LPS sensing. Therefore, an epithelial cell-intrinsic noncanonical inflammasome plays a critical role in antimicrobial defense at the intestinal mucosal surface.
authors.affiliation: Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-7090, USA; Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT 59840, USA. Electronic address: lknodler@vetmed.wsu.edu.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Knodler
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver BC V6H 3V4, Canada.
authors.forename: Shauna M
authors.initials: SM
authors.lastname: Crowley
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver BC V6H 3V4, Canada.
authors.forename: Ho Pan
authors.initials: HP
authors.lastname: Sham
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver BC V6H 3V4, Canada.
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-7090, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Wrande
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver BC V6H 3V4, Canada.
authors.forename: Caixia
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.affiliation: Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT 59840, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Steele-Mortimer
authors.affiliation: Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-7090, USA; Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT 59840, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Celli
authors.affiliation: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver BC V6H 3V4, Canada. Electronic address: bvallance@cw.bc.ca.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator / Q000378:metabolism*; D045744:Cell Line, Tumor; D054308:Enteropathogenic Escherichia coli / Q000276:immunology; D004789:Enzyme Activation; D004927:Escherichia coli Infections / Q000201:enzymology* / Q000276:immunology; D005759:Gastroenteritis / Q000201:enzymology / Q000382:microbiology; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D020382:Interleukin-18 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012480:Salmonella Infections / Q000201:enzymology* / Q000276:immunology; D019779:Salmonella enterica / Q000276:immunology
chemical_list: C000589760:IL18 protein, human; D058847:Inflammasomes; D020382:Interleukin-18; D008070:Lipopolysaccharides; C093516:CASP4 protein, human; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator