Epithelial Cell Extrusion Leads to Breaches in the Intestinal Epithelium

Liu, Julia J.; Davis, Elisabeth M.; Wine, Eytan; Lou, Yuefei; Rudzinski, J; Alipour, Misagh; Boulanger, Pierre; Thiesen, Aducio; Sergi, Consolato; Fedorak, Richard N.; Muruve, Daniel A.; Madsen, Karen; Irvin, Randall T.

doi:10.1097/mib.0b013e3182807600

Cited by 27 publications

(18 citation statements)

References 51 publications

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“…Caspase 1 is activated in human IBD including CD and UC. 13, 14 IL-1β and/or IL-18 is consistently produced in UC samples compared to non-IBD controls. 13, 14, 27, 28 However, studies using chemically-induced IBD models (e.g.…”

Section: Discussionmentioning

confidence: 94%

“…13, 14, 27, 28 To characterize which inflammasomes are expressed in human UC and colon cancer, we performed immunostaining for Caspase 1 and ASC on colon sections from UC and cancer patients, and healthy controls (Figure 7B). Similar to mouse colon, ASC staining was similar in healthy, UC and colorectal cancer tissue (Figure 7B).…”

Section: Resultsmentioning

confidence: 99%

“…13, 14,3, 15 Caspases 1 and 11 are key components of canonical and non-canonical inflammasomes, respectively, which are multiprotein complexes whose formation is dependent on diverse stimuli of microbial, environmental, or endogenous origin, and usually require additional components including members of the Nod-like receptor (NLR) family and adaptor proteins. 16 Both types of inflammasomes function to activate caspase 1 or 11 leading to proteolytic processing of proIL-1β and proIL-18 that are then secreted and promote inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice

et al. 2016

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BACKGROUND & AIMS Core 1- and 3-derived mucin-type O-linked oligosaccharides (O-glycans) are major components of the colonic mucus layer. Defective forms of colonic O-glycans, such as Tn antigen, are frequently observed in patients with ulcerative colitis and colorectal cancer, but it is not clear if they contribute to pathogenesis. We investigated whether and how impaired O-glycosylation contributes to development of colitis-associated colorectal cancer using mice lacking intestinal core 1- and 3-derived O-glycans. METHODS We generated mice that lack the core 1- and 3-derived intestinal O-glycans (DKO mice) and analyzed them, along with mice that lack the intestinal epithelial core 1 O-glycans (IEC C1galt1−/− mice) or mice that lack core 3 O-glycans (C3Gnt−/− mice). Intestinal tissues were collected at different time points and analyzed for levels of mucin and Tn antigen, development of colitis, and tumor formation using imaging, quantitative PCR, immunoblot, and ELISA techniques. We also used cellular and genetic approaches, as well as intestinal microbiota depletion, to identify inflammatory mediators and pathways that contribute to disease in DKO and wild-type littermates (controls). RESULTS Intestinal tissues from DKO mice contained higher levels of Tn antigen and had more severe spontaneous chronic colitis than tissues from IEC C1galt1−/− mice, whereas spontaneous colitis was absent in C3GnT−/− and control mice. IEC C1galt1−/− mice and DKO mice developed spontaneous colorectal tumors, although the onset of tumors in the DKO mice was earlier (age 8–9 months) than that in IEC C1galt1−/− mice (around age 12 months). Antibiotic depletion of the microbiota did not cause loss of Tn antigen but did reduce the development of colitis and cancer formation in DKO mice. Colon tissues from DKO mice, but not control mice, contained active forms of caspase-1 and increased caspase-11, which were reduced after antibiotic administration. Supernatants from colon tissues of DKO mice contained increased levels of interleukin-1β and interleukin-18, compared to those from control mice. Disruption of the caspase 1 and caspase 11 genes in DKO mice (DKO/Casp1/11−/− mice) decreased development of colitis, characterized by reduced colonic thickening, hyperplasia, and inflammatory infiltrate, compared with DKO mice. CONCLUSIONS Impaired expression of O-glycans causes colonic mucus barrier breach and subsequent microbiota-mediated activation of caspase 1-dependent inflammasomes in colonic epithelial cells of mice. These processes could contribute to colitis-associated colon cancer in humans.

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice

et al. 2016

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“…For example, the cell signalingcontrolled shedding of intestinal polarized epithelial cells that occurs in vivo during the renewal of the intestinal epithelium has never been observed in fully differentiated colon cancer cells forming a monolayer. Only a recent report describes the extrusion of cells from a fully differentiated T84 cell monolayer induced by the caspase-1-dependent action of nigericine (837). It is noteworthy that the extrusion of cells from fully differentiated colon cancer cell monolayers by enterovirulent bacteria, which is known to induce caspase-dependent cell death, currently has not been documented.…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of Human Enterovirulent Bacteria: Lessons from Cultured, Fully Differentiated Human Colon Cancer Cell Lines

Moal

Servin

2013

Microbiol Mol Biol Rev

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SUMMARY Hosts are protected from attack by potentially harmful enteric microorganisms, viruses, and parasites by the polarized fully differentiated epithelial cells that make up the epithelium, providing a physical and functional barrier. Enterovirulent bacteria interact with the epithelial polarized cells lining the intestinal barrier, and some invade the cells. A better understanding of the cross talk between enterovirulent bacteria and the polarized intestinal cells has resulted in the identification of essential enterovirulent bacterial structures and virulence gene products playing pivotal roles in pathogenesis. Cultured animal cell lines and cultured human nonintestinal, undifferentiated epithelial cells have been extensively used for understanding the mechanisms by which some human enterovirulent bacteria induce intestinal disorders. Human colon carcinoma cell lines which are able to express in culture the functional and structural characteristics of mature enterocytes and goblet cells have been established, mimicking structurally and functionally an intestinal epithelial barrier. Moreover, Caco-2-derived M-like cells have been established, mimicking the bacterial capture property of M cells of Peyer's patches. This review intends to analyze the cellular and molecular mechanisms of pathogenesis of human enterovirulent bacteria observed in infected cultured human colon carcinoma enterocyte-like HT-29 subpopulations, enterocyte-like Caco-2 and clone cells, the colonic T84 cell line, HT-29 mucus-secreting cell subpopulations, and Caco-2-derived M-like cells, including cell association, cell entry, intracellular lifestyle, structural lesions at the brush border, functional lesions in enterocytes and goblet cells, functional and structural lesions at the junctional domain, and host cellular defense responses.

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“…In this issue of Digestive Diseases and Sciences, Liu et al [5] address the issue of whether the density of gaps detected with CLE correlates with quantitative analysis of activated caspase in conventional mucosal biopsies from patients. The basis of this study is that epithelial cells undergoing apoptotic cell death during the shedding process activate an enzyme termed caspase 3 while cells undergoing necrosis or pyroptosis during shedding activate caspase 1 [6]. The investigators recruited 13 patients with either Crohn's disease, ulcerative colitis or diarrhea-predominant irritable bowel disease (IBS) and 12 control patients who were undergoing conventional colonoscopy either for evaluation of symptoms or colorectal cancer screening.…”

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confidence: 99%

Confocal Laser Endomicroscopy in the Management of IBD: Clearly Superior?

Watson

2016

Dig Dis Sci

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Epithelial Cell Extrusion Leads to Breaches in the Intestinal Epithelium

Abstract: IEC extrusion mediated by caspase-1 activation contributes to altered intestinal permeability in vitro and in vivo.

Cited by 27 publications

References 51 publications

Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice

Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice

Pathogenesis of Human Enterovirulent Bacteria: Lessons from Cultured, Fully Differentiated Human Colon Cancer Cell Lines

Confocal Laser Endomicroscopy in the Management of IBD: Clearly Superior?

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