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

English version

Autoři: Minori Kubota ^aff001; Kazuki Kakimoto ^aff001; Takatoshi Nakagawa ^aff002; Eiko Koubayashi ^aff001; Kei Nakazawa ^aff001; Hideki Tawa ^aff001; Yuki Hirata ^aff001; Toshihiko Okada ^aff001; Ken Kawakami ^aff001; Akira Asai ^aff001; Shuhei Hosomi ^aff003; Toshihisa Takeuchi ^aff001; Shinya Fukunishi ^aff001; Takuya Inoue ^aff001; Michio Asahi ^aff002; Kazuhide Higuchi ^aff001
Působiště autorů: 2nd Department of Internal Medicine, Osaka Medical College, Daigakumachi, Takatsuki, Osaka, Japan ^aff001; Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Daigakumachi, Takatsuki, Osaka, Japan ^aff002; Department of Gastroenterology, Osaka City University Graduate School of Medicine, Asahimachi, Abeno-ku, Osaka, Japan ^aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0225066

Souhrn

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 (Atg5^flox/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 Atg5^flox/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-κB 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.

Klíčová slova:

Cytokines – Autophagic cell death – Gastrointestinal tract – Mouse models – Apoptosis – Inflammatory bowel disease – MAPK signaling cascades – Colitis

Zdroje

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