Abstract
Activation of the noncanonical inflammasome, mediated by caspase-11, serves as an additional pathway for the production of the proinflammatory cytokines IL-1β and IL-18. Noncanonical inflammasome activity occurs during host defense against Gram-negative bacteria and in models of acute septic shock. We propose that the noncanonical inflammasome is activated in mice during acute intestinal inflammation elicited by dextran sodium sulfate (DSS), a model of experimental colitis. We find that caspase-11−/− mice display enhanced susceptibility to DSS, because of impaired IL-18 production. The impaired IL-18 levels observed are shown to result in reduced intestinal epithelial cell proliferation and increased cell death. We also suggest that a novel type II IFN–dependent, type I IFN-TRIF–independent signaling pathway is required for in vivo caspase-11 production in intestinal epithelial cells during DSS colitis. Collectively, these data suggest that IFN-γ–mediated caspase-11 expression has a key role maintaining intestinal epithelial barrier integrity in vivo during experimentally induced acute colitis.
Highlights
Activation of the noncanonical inflammasome, mediated by caspase-11, serves as an additional pathway for the production of the proinflammatory cytokines IL-1b and IL-18
The recent association of caspase-11 with a noncanonical inflammasome, combined with the knowledge that previous studies reporting a role for caspase-1 in colitis models of intestinal inflammation were likely carried out on Casp1,Casp11 doubleknockout mice [14,15,16], led us to investigate the involvement of caspase-11 in intestinal inflammation
Caspase-11–mediated IL-1a production has recently been shown to stimulate neutrophil recruitment in vivo during bacterial infection of mice, suggesting that caspase-11 may be responsible for recruiting neutrophils to sites of intestinal damage during dextran sodium sulfate (DSS)-induced colon inflammation [21], this was not examined during our study
Summary
Activation of the noncanonical inflammasome, mediated by caspase-11, serves as an additional pathway for the production of the proinflammatory cytokines IL-1b and IL-18. We propose that the noncanonical inflammasome is activated in mice during acute intestinal inflammation elicited by dextran sodium sulfate (DSS), a model of experimental colitis. We suggest that a novel type II IFN– dependent, type I IFN-TRIF–independent signaling pathway is required for in vivo caspase-11 production in intestinal epithelial cells during DSS colitis. These data suggest that IFN-g–mediated caspase-11 expression has a key role maintaining intestinal epithelial barrier integrity in vivo during experimentally induced acute colitis. Abbreviations used in this article: BMDM, bone marrow–derived macrophage; DSS, dextran sodium sulfate; IEC, intestinal epithelial cell; PCNA, proliferating cell nuclear Ag; WT, wild type
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