Protective Role for Caspase-11 during Acute Experimental Murine Colitis

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.

Inflammasomes of the intestinal epithelium

“…Mouse caspase-11 appears predominantly expressed in macrophages [2]; yet detectable levels have been noted in IECs enriched from mice exposed to DSS [56,57]. Human caspase-4, by contrast, shows a wider expression pattern across cell types, including high steady-state levels in IECs and other epithelial cells [55,58,59].…”

“…In one study, this phenotype was linked to attenuated IL-18 production, could be counteracted by recombinant IL-18 administration, and involved skewing of epithelial proliferation/regeneration [56]. A parallel study reached similar conclusions regarding the functional impact of caspase-11 on colitis, but found no obvious defect in mucosal production of either IL-1b or IL-18 [57].…”

Converging roles of caspases in inflammasome activation, cell death and innate immunity

“…How NLRC4 and NLRP3 differentially coordinate caspase 1 functions to achieve IL-18-dependent and -independent effects during colorectal tumorigenesis is largely unknown. Recent studies have also demonstrated a requirement for caspase 11 in mediating resistance against dextran sulfate sodium (DSS)-induced intestinal inflammation in mice 69-71 . Whether IL-1β and IL-18 are contributing factors in this case is contentious, with both similar and reduced levels of IL-1β and IL-18 being reported in caspase 11-deficient mice treated with DSS compared with treated wild-type mice 70, 71 .…”

The Inflammatory Caspases-1 and -11 Mediate the Pathogenesis of Dermatitis in Sharpin-Deficient Mice

“…Active caspase-1 cleaves a number of substrates, including the cytokines pro-IL-1b and pro-IL-18, to initiate the inflammatory cascade and, in some contexts, a rapid form of cell death termed "pyroptosis." The related protease caspase-11 (human caspase-4) also was implicated in the induction of pyroptosis (1) and cytokine production (2,3) in response to microbial stimuli, such as Escherichia coli, Citrobacter rodentium, or Vibrio cholera, or in the context of chemically induced colitis. Caspase-11 also was shown to confer protection from bacteria that escape the phagosome (4-7), and it acts as a direct sensor of intracellular LPS (8).…”