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Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation.

ABSTRACT: BACKGROUND AND AIM:Autophagy is an essential process involved in the pathogenesis of inflammatory bowel disease (IBD). Although there are many data showing the roles of autophagy in intestinal epithelial cells (IECs), the mechanisms involved remain to be fully elucidated. We investigated the influence of autophagy in IECs on gastrointestinal tract inflammation. METHODS:Mice with conditional knockout of Atg5 in IECs (Atg5flox/flox/villin-Cre mice) were subjected to dextran sulfate sodium (DSS)-induced colitis and analyzed for colitis susceptibility. Additionally, we used Atg5-silenced rat IECs (IEC6shAtg5 cells) for in vitro assays. RESULTS:Sensitivity to DSS markedly increased in Atg5flox/flox/villin-Cre mice compared to that in wild-type mice. In IEC6shAtg5 cells, apoptosis was enhanced, and cell viability significantly decreased compared to IEC-6 cells. The expression of proinflammatory cytokines increased upon suppression of autophagy. Furthermore, silencing of Atg5 was associated with inflammation of IECs, activation of the mitogen-activated protein kinase (MAPK) signaling pathway by the intracellular reactive oxygen species accumulation, and NF-?B p65 phosphorylation. CONCLUSIONS:Autophagy in IECs plays an essential role in the maintenance of intestinal homeostasis, and autophagy deficiency triggers inflammation. Development of methods targeting autophagy might be beneficial in the treatment of IBD.

SUBMITTER: Kubota M

PROVIDER: S-EPMC6839862 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation.

Kubota Minori M Kakimoto Kazuki K Nakagawa Takatoshi T Koubayashi Eiko E Nakazawa Kei K Tawa Hideki H Hirata Yuki Y Okada Toshihiko T Kawakami Ken K Asai Akira A Hosomi Shuhei S Takeuchi Toshihisa T Fukunishi Shinya S Inoue Takuya T Asahi Michio M Higuchi Kazuhide K

PloS one 20191108 11

<h4>Background and aim</h4>Autophagy is an essential process involved in the pathogenesis of inflammatory bowel disease (IBD). Although there are many data showing the roles of autophagy in intestinal epithelial cells (IECs), the mechanisms involved remain to be fully elucidated. We investigated the influence of autophagy in IECs on gastrointestinal tract inflammation.<h4>Methods</h4>Mice with conditional knockout of Atg5 in IECs (Atg5flox/flox/villin-Cre mice) were subjected to dextran sulfate ...[more]

PMID: 31703091

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Project description:The endoribonuclease RNase-L is a type-I interferon (IFN)-regulated component of the innate immune response that functions in antiviral, antibacterial, and antiproliferative activities. RNase-L produces RNA agonists of RIG-I-like receptors, sensors of cytosolic pathogen-associated RNAs that induce cytokines including IFN-?. IFN-? and RIG-I-like receptors signaling mediate protective responses against experimental colitis and colitis-associated cancer and contribute to gastrointestinal homeostasis. Therefore, we investigated a role for RNase-L in murine colitis and colitis-associated cancer and its association with RIG-I-like receptors signaling in response to bacterial RNA.Colitis was induced in wild type-deficient and RNase-L-deficient mice (RNase-L?/?) by administration of dextran sulfate sodium (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM). Histological analysis and immunohistochemistry were performed on colon tissue to analyze immune cell infiltration and tissue damage after induction of colitis. Expression of cytokines was measured by quantitative real-time-PCR and ELISA.DSS-treated RNase-L?/? mice exhibited a significantly higher clinical score, delayed leukocyte infiltration, reduced expression of IFN-?, tumor necrosis factor ?, interleukin-1?, and interleukin-18 at early times post-DSS exposure, and increased mortality as compared with wild-type mice. DSS/AOM-treated RNase-L?/? mice displayed an increased tumor burden. Bacterial RNA triggered IFN-? production in an RNase-L-dependent manner and provided a potential mechanism by which RNase-L contributes to the gastrointestinal immune response to microbiota and protects against experimental colitis and colitis-associated cancer.RNase-L promotes the innate immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer. The RNase-L-dependent production of IFN-? stimulated by bacterial RNA may be a mechanism to protect against gastrointestinal inflammatory disease.

Dataset Information

Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation.

Publications

Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation.

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