Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice

Murphy, SB; Rhee, Lesley; Grimm, Wesley A; Weber, Christopher R.; Messer, Jeannette S.; Lodolce, James P.; Chang, Jonathan; Bartulis, Sarah; Nero, Thomas M.; Kukla, Renata A.; MacDougall, Gordon; Binghay, Charles; Kolodziej, Lauren; Boone, David L.

doi:10.1152/ajpgi.00020.2014

Cited by 18 publications

(27 citation statements)

References 44 publications

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“…IL-10 is a potent immunosuppressive molecule that mediates the down-regulation of Th1 responses by inhibiting the production of proinflammatory cytokines. The crucial role of IL-10 in the intestine was established based on the finding that IL-10-deficient mice spontaneously developed enterocolitis [26,[30][31][32]. In addition, IL-10 inhibits NF-κB activation in human monocytes [33].…”

Section: Discussionmentioning

confidence: 99%

Cathelicidin-BF suppresses intestinal inflammation by inhibiting the nuclear factor-κB signaling pathway and enhancing the phagocytosis of immune cells via STAT-1 in weanling piglets

Zhang

et al. 2015

International Immunopharmacology

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Section: Discussionmentioning

confidence: 99%

Cathelicidin-BF suppresses intestinal inflammation by inhibiting the nuclear factor-κB signaling pathway and enhancing the phagocytosis of immune cells via STAT-1 in weanling piglets

Zhang

et al. 2015

International Immunopharmacology

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“…TNF-Induced Apoptosis in A20 Tg Mice. A20 expression in IECs was reported to either restrain apoptosis and maintain barrier function (9,18) or promote development of colitis (11), two diametrically opposed outcomes, neither of which is fully consistent with A20-mediated inhibition of NF-κB signaling. To determine how elevated A20 affects the viability of TNF-exposed IECs, we used villin-Tnfaip3 (hereafter A20) Tg mice (18).…”

Section: Significancementioning

confidence: 90%

“…TNF-Induced Apoptosis in A20-Expressing Enteroids. A20 Tg mice that are IL-10-deficient exhibit defective expression of mucosal cytokines and antimicrobial peptides, resulting in microbial colonization of the inner mucus layer, along with microbial dysbiosis (11). To assess IEC-autonomous A20 effects, we used enteroid (intestinal organoid) cultures, which retain normal epithelial differentiation and are free of microbes and immune cells (19).…”

Section: Significancementioning

confidence: 99%

“…Curiously, however, mice with enterocyte-specific A20 deletion are hypersensitive to dextran sodium sulfate (DSS)induced colitis and TNF-induced epithelial apoptosis (9), effects that are inconsistent with the known ability of A20 to suppress activation of NF-κB (10), which promotes IEC survival (7). Another puzzling finding is induction of early-onset colitis by transgenic (Tg) A20 in IL-10-deficient mice (11). The same A20 Tg mice, however, are protected from DSS-induced, but not 2,4,6-trinitrobenzenesulfonic acid-induced, colitis (12).…”

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confidence: 99%

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Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death

Garcia-Carbonell

Wong

Kim

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.

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“…[4][5][6][7][8][9][10] They are regulated by various factors such as the intestinal microbiota, 11 food, 12,13 and intrinsic factors, including mucosal perfusion, [14][15][16] nerves, 17,18 and components of the immune system. 19,20 Their usage is limited because the measurement requires intestinal tissue samples that cannot be easily obtained from healthy or diseased individuals. In mice, the availability of such samples is less problematic, but the measurements are hampered by a lack of standardization.…”

Section: Introductionmentioning

confidence: 99%

Intestinal barrier analysis by assessment of mucins, tight junctions, and α-defensins in healthy C57BL/6J and BALB/cJ mice

et al. 2016

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The intestinal barrier is gaining increasing attention because it is related to intestinal homeostasis and disease. Different parameters have been used in the past to assess intestinal barrier functions in experimental studies; however most of them are poorly defined in healthy mice. Here, we compared a number of barrier markers in healthy mice, established normal values and correlations. In 48 mice (24 C57BL/6J, 24 BALB/cJ background), we measured mucus thickness, and expression of mucin-2, α-defensin-1 and -4, zonula occludens-1, occludin, junctional adhesion molecule-A, claudin-1, 2 and -5. We also analyzed claudin-3 and fatty acid binding protein-2 in urine and plasma, respectively. A higher expression of mucin-2 protein was found in the colon compared to the ileum. In contrast, the α-defensins-1 and -4 were expressed almost exclusively in the ileum. The protein expression of the tight junction molecules claudin-1, occludin and zonula occludens-1 did not differ between colon and ileum, although some differences occurred at the mRNA level. No age- or gender-related differences were found. Differences between C57BL/6J and BALB/cJ mice were found for α-defensin-1 and -4 mRNA expression, and for urine and plasma marker concentrations. The α-defensin-1 mRNA correlated with claudin-5 mRNA, whereas α-defensin-4 mRNA correlated with claudin-3 concentrations in urine. In conclusion, we identified a number of murine intestinal barrier markers requiring tissue analyses or measurable in urine or plasma. We provide normal values for these markers in mice of different genetic background. Such data might be helpful for future animal studies in which the intestinal barrier is of interest.

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Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice

Abstract: DL. Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice.

Cited by 18 publications

References 44 publications

Cathelicidin-BF suppresses intestinal inflammation by inhibiting the nuclear factor-κB signaling pathway and enhancing the phagocytosis of immune cells via STAT-1 in weanling piglets

Cathelicidin-BF suppresses intestinal inflammation by inhibiting the nuclear factor-κB signaling pathway and enhancing the phagocytosis of immune cells via STAT-1 in weanling piglets

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death

Intestinal barrier analysis by assessment of mucins, tight junctions, and α-defensins in healthy C57BL/6J and BALB/cJ mice

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