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Caspase-11 is expressed in the colonic mucosa and protects against dextran sodium sulfate-induced colitis.

ABSTRACT: 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)-1? and IL-18, whereas IL-1? 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.

SUBMITTER: Demon D

PROVIDER: S-EPMC4205216 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Caspase-11 is expressed in the colonic mucosa and protects against dextran sodium sulfate-induced colitis.

Demon D D Kuchmiy A A Fossoul A A Zhu Q Q Kanneganti T-D TD Lamkanfi M M

Mucosal immunology 20140521 6

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 ...[more]

PMID: 24850431

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Project description:BackgroundChronic inflammation is well known to be a risk factor for colon cancer. Previously we established a novel mouse model of inflammation-related colon carcinogenesis, which is useful to examine the involvement of inflammation in colon carcinogenesis. To shed light on the alterations in global gene expression in the background of inflammation-related colon cancer and gain further insights into the molecular mechanisms underlying inflammation-related colon carcinogenesis, we conducted a comprehensive DNA microarray analysis using our model.MethodsMale ICR mice were given a single ip injection of azoxymethane (AOM, 10 mg/kg body weight), followed by the addition of 2% (w/v) dextran sodium sulfate (DSS) to their drinking water for 7 days, starting 1 week after the AOM injection. We performed DNA microarray analysis (Affymetrix GeneChip) on non-tumorous mucosa obtained from mice that received AOM/DSS, AOM alone, and DSS alone, and untreated mice at wks 5 and 10.ResultsMarkedly up-regulated genes in the colonic mucosa given AOM/DSS at wk 5 or 10 included Wnt inhibitory factor 1 (Wif1, 48.5-fold increase at wk 5 and 5.7-fold increase at wk 10) and plasminogen activator, tissue (Plat, 48.5-fold increase at wk 5), myelocytomatosis oncogene (Myc, 3.0-fold increase at wk 5), and phospholipase A2, group IIA (platelets, synovial fluid) (Plscr2, 8.0-fold increase at wk 10). The notable down-regulated genes in the colonic mucosa of mice treated with AOM/DSS were the peroxisome proliferator activated receptor binding protein (Pparbp, 0.06-fold decrease at wk 10) and the transforming growth factor, beta 3 (Tgfb3, 0.14-fold decrease at wk 10). The inflammation-related gene, peroxisome proliferator activated receptor gamma (Ppargamma 0.38-fold decrease at wk 5), was also down-regulated in the colonic mucosa of mice that received AOM/DSS.ConclusionThis is the first report describing global gene expression analysis of an AOM/DSS-induced mouse colon carcinogenesis model, and our findings provide new insights into the mechanisms of inflammation-related colon carcinogenesis and the establishment of novel therapies and preventative strategies against carcinogenesis.

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Caspase-11 is expressed in the colonic mucosa and protects against dextran sodium sulfate-induced colitis.

Publications

Caspase-11 is expressed in the colonic mucosa and protects against dextran sodium sulfate-induced colitis.

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