Caspase-11 is expressed in the colonic mucosa and protects against dextran sodium sulfate-induced colitis.
Ulcerative colitis and Crohn's disease are major inflammatory syndromes that affect millions of patients. Caspase-11 confers protection against Gram-negative enteropathogens, but its role during colitis is unknown. Here, we show that caspase-11 was constitutively expressed in the colon, and that caspase-11-deficient (caspase-11(-/-)) mice were hypersusceptible to dextran sodium sulfate (DSS)-induced colitis. Notably, pro-inflammatory Prevotella species were strongly reduced in the gut microbiota of caspase-11(-/-) mice. Co-housing with wild-type mice leveled Prevotella contents, but failed to protect caspase-11(-/-) mice from increased susceptibility to DSS-induced colitis. We therefore addressed the role of caspase-11 in immune signaling. DSS-induced tissue damage and inflammatory cell infiltration in the gut were markedly increased in caspase-11−/− mice, while release of the pyroptosis/necroptosis marker HMGB1 was abolished [Corrected]. Moreover, caspase-11(-/-) mice showed normal or increased production of mature interleukin (IL)-1β and IL-18, whereas IL-1β and IL-18 secretion was blunted in animals lacking both caspases 1 and 11. In conclusion, we showed that caspase-11 shapes the gut microbiota composition, and that caspase-11(-/-) mice are highly susceptible to DSS-induced colitis. Moreover, DSS-induced inflammasome activation relied on caspase-1, but not caspase-11. These results suggest a role for other caspase-11 effector mechanisms such as pyroptosis in protection against intestinal inflammation.
1] Department of Medical Protein Research, VIB, Ghent, Belgium [2] Department of Biochemistry, Ghent University, Ghent, Belgium.
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Demon
1] Department of Medical Protein Research, VIB, Ghent, Belgium [2] Department of Biochemistry, Ghent University, Ghent, Belgium.
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Kuchmiy
1] Department of Medical Protein Research, VIB, Ghent, Belgium [2] Department of Biochemistry, Ghent University, Ghent, Belgium.
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Fossoul
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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Zhu
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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Kanneganti
1] Department of Medical Protein Research, VIB, Ghent, Belgium [2] Department of Biochemistry, Ghent University, Ghent, Belgium.
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Lamkanfi
D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D053471:Caspases, Initiator; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D020022:Genetic Predisposition to Disease; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018720:Prevotella / Q000276:immunology
C587672:IL1B protein, mouse; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D016264:Dextran Sulfate; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1