RRC ID 59774
Author Kubota M, Kakimoto K, Nakagawa T, Koubayashi E, Nakazawa K, Tawa H, Hirata Y, Okada T, Kawakami K, Asai A, Hosomi S, Takeuchi T, Fukunishi S, Inoue T, Asahi M, Higuchi K.
Title Autophagy deficiency exacerbates colitis through excessive oxidative stress and MAPK signaling pathway activation.
Journal PLoS One
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-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.
Volume 14(11)
Pages e0225066
Published 2019-1-1
DOI 10.1371/journal.pone.0225066
PII PONE-D-19-16281
PMID 31703091
PMC PMC6839862
MeSH Animals Apoptosis / genetics Autophagy* Autophagy-Related Protein 5 / genetics Cell Line Cell Survival / genetics Colitis / metabolism* Cytokines / metabolism Disease Models, Animal Gene Knockdown Techniques Inflammation Mediators / metabolism Inflammatory Bowel Diseases / etiology Inflammatory Bowel Diseases / metabolism Inflammatory Bowel Diseases / pathology MAP Kinase Signaling System* Mice Mice, Knockout NF-kappa B / metabolism Oxidative Stress* Reactive Oxygen Species / metabolism
IF 2.776
Times Cited 0
Human and Animal Cells IEC 6(RCB0993)