Enhanced sensitivity to DSS colitis caused by a hypomorphic
            <i>Mbtps1</i>
            mutation disrupting the ATF6-driven unfolded protein response

Brandl, Katharina; Rutschmann, Sophie; Li, Xiaohong; Du, Xin; Xiao, Nengming; Schnabl, Bernd; Brenner, David A.; Beutler, Bruce

doi:10.1073/pnas.0813036106

Cited by 122 publications

(120 citation statements)

References 27 publications

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“…Generation of BM chimeric mice was performed as recently described (34). Recipient WT (CD45.1) or Myd88 −/− ; Trif Lps2/Lps2 or Adam17 wavedX/wavedX (CD45.2) mice were lethally irradiated with 950 rad using a 137 Cs source and injected i.v.…”

Section: Methodsmentioning

confidence: 99%

“…Sex-and agematched littermates received 2% DSS (MP Biomedicals) in drinking water for 6-7 d. Weight was recorded daily. Gut commensal depletion was performed as described previously (34). In some experiments, mice were given daily doses (10 μg per mouse) of recombinant AREG (Leinco Technologies) or PBS by i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Colonic epithelial cells of WT and Myd88 −/− / Trif Lps2/Lps2 double-deficient mice were isolated as described previously (34).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands

Brandl

Sun

Neppl

et al. 2010

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

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134

129

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Toll-like receptors (TLRs) trigger intestinal inflammation when the epithelial barrier is breached by physical trauma or pathogenic microbes. Although it has been shown that TLR-mediated signals are ultimately protective in models of acute intestinal inflammation [such as dextran sulfate sodium (DSS)-induced colitis], it is less clear which cells mediate protection. Here we demonstrate that TLR signaling in the nonhematopoietic compartment confers protection in acute DSS-induced colitis. Epithelial cells of MyD88/Trif-deficient mice express diminished levels of the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG), and systemic lipopolysaccharide administration induces their expression in the colon. N -ethyl- N -nitrosourea (ENU)-induced mutations in Adam17 (which is required for AREG and EREG processing) and in Egfr both produce a strong DSS colitis phenotype, and the Adam17 mutation exerts its deleterious effect in the nonhematopoietic compartment. The effect of abrogation of TLR signaling is mitigated by systemic administration of AREG. A TLR→MyD88→AREG/EREG→EGFR signaling pathway is represented in nonhematopoietic cells of the intestinal tract, responds to microbial stimuli once barriers are breached, and mediates protection against DSS-induced colitis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands

Brandl

Sun

Neppl

et al. 2010

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

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134

129

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“…Restoration of intestinal homeostasis requires several factors, including epithelial cell proliferation and differentiation, vesicle trafficking, protein secretion, integrity of the unfolded protein response pathways, and immune signaling (4)(5)(6)(7)(8). The essential molecular components required for a physiological response to the damage caused by DSS can be revealed by random germline mutagenesis (4).…”

mentioning

confidence: 99%

Creatine maintains intestinal homeostasis and protects against colitis

Turer

McAlpine

Wang

et al. 2017

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

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Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea–mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted (Gatmc/c) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatmc/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatmc/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury.

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“…Specifically, in the APC min± model, modulation of gut permeability by DSS 25 results in exacerbation of inflammatory activity and promotes tumorigenesis in the colon. 26 Therefore, to determine whether the IL-10- and/or IL-12-IFNγ-epithelial barrier axis played a role in the observed synergy, we undertook examination of gut epithelial barrier function in different treatment groups.…”

Section: Resultsmentioning

confidence: 99%

Enhanced gut barrier integrity sensitizes colon cancer to immune therapy

Bhutiani

Anderson

et al. 2018

OncoImmunology

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Oral IL-10 suppressed tumor growth in the APCmin/+ mouse/Bacteroides fragilis colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cytokines mediated distinct immunological effects in the gut, i.e. IL-10 diminished Th17 cell prevalence whereas IL-12 induced IFNγ and enhanced CD8 + T-cell activity. Loss-of-function studies demonstrated that IL-12-driven CD8 + T-cell expansion was only partially responsible for the synergy, and that both the detrimental and the beneficial activities of IL-12 required IFNγ. Examination of colon physiology in mice receiving single vs dual treatment revealed that exacerbation of disease by IL-12 monotherapy was associated with compromised gut barrier integrity whereas combined treatment reversed this effect, uncovering additional activity by the cytokines on the stroma. Further analysis showed that the stromal effects of IL-12 included a 6-fold increase in IL-10RA expression in the colon epithelium, linking the epithelial activity of the cytokines. Finally, dual but not monotherapy induced a 3-fold increase in tight junction protein levels in the colon, identifying the mechanism by which IL-10 blocked the detrimental effect of the IL-12-IFNγ axis on barrier function without interfering with its beneficial immunological activity. These findings establish that the synergy between IL-12 and IL-10 was mediated by pleiotropic effects on the immune and the non-immune compartments and that the latter activity was critical to therapeutic outcome.

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Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response

Cited by 122 publications

References 27 publications

MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands

MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands

Creatine maintains intestinal homeostasis and protects against colitis

Enhanced gut barrier integrity sensitizes colon cancer to immune therapy

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