Targeted deletion of Atg5 in intestinal epithelial cells promotes dextran sodium sulfate-induced colitis

Abstract

Autophagy associated genes have been identified as susceptible loci for inflammatory bowel disease. We investigated the role of a core autophagy factor, Atg5, in the development of dextran sodium sulfate (DSS) induced colitis. Intestinal epithelial cell (IEC) specific Atg5 gene deficient mice (Atg5 ΔIEC mice) were generated by cross of Atg5 floxed mice (Atg5 fl/fl) with transgenic mice expressing Cre recombinase driven by the villin promotor. Mice were given three cycles of 1.5% DSS in drinking water for 5 days and regular water for 14 days over a 60 day period. The dysfunc tion of autophagy characterized by a marked accumulation of p62 protein, a substrate for autophagy degradation, was detected in epithelial cells in the non inflamed and inflamed mucosa of inflammatory bowel disease patients. DSS colitis was exacerbated in Atg5 ΔIEC mice compared to control Atg5 fl/fl mice. Phosphorylation of inositol requiring transmembrane kinase/endonuclease1α (IRE1α), a sensor for endoplasmic reticulum stress, and c Jun N terminal kinase, a downstream target of IRE1α, were significantly enhanced in IECs in DSS treated Atg5 ΔIEC mice. Accumulation of phosphorylated IRE1α was enhanced by the treatment with chloroquine, an autophagy inhibitor. Apoptotic IECs were more abundant in DSS treated Atg5 ΔIEC mice. These findings suggest that Atg5 suppresses endoplasmic reticulum stress induced apoptosis of IECs via the degradation of excess p IRE1α.

RETRACTED ARTICLE: MicroRNA-335-5p alleviates inflammatory response, airway fibrosis, and autophagy in childhood asthma through targeted regulation of autophagy related 5

“…Further experiments revealed that miR-335-5p exerts biological functions through targeting ATG5. ATG5, an essential autophagosome formation-related protein, modulates various signal pathways like IFN-I, and p53/Rb [ 36 ], and is relative to tumorigenesis and inflammation [ 37 ]. In asthma studies, there is a positive correlation between ATG5 and various collagen gene expression [ 38 ].…”

Quercetin Ameliorates Lipopolysaccharide-Induced Duodenal Inflammation through Modulating Autophagy, Programmed Cell Death and Intestinal Mucosal Barrier Function in Chicken Embryos

“…LC3-1 is converted to LC3-2, which is essential in the elongation and closure of the autophagosome membrane for the initiation of autophagy. Nishino et al found DSS-induced colitis was exacerbated in ATG5 deletion mice [ 39 ]. Our results show that the mRNA and relative protein expressions of ATG5, LC3-1, and LC3-2 were increased after LPS challenge, and downregulated by quercetin.…”

Role of autophagy in aging: The good, the bad, and the ugly

“…ATG5 is involved in the development of B lymphocytes, as a guardian of immune integrity, in kertain K5 expression in epithelia. This autophagy gene is also important for the prevention of osteoarthritis, cataract, dextran sodium sulfate‐induced colitis and autophagic cell death and in the elimination of mitochondria from embryonic reticulocytes (Morgan‐Bathke et al, 2013 , Honda et al, 2014 , Baerga et al, 2009 , Sukseree et al, 2013 , Ye et al, 2018 , Mizushima et al, 2011 , Miller et al, 2008 , Pyo et al, 2005 , Nishino et al, 2021 ). Deletion of Atg7 has shown a role for this autophagy gene in adipogenesis, hyperglycemia, glucose intolerance, and hypo‐insulinemia, disorders that are common in aging (Bouderlique et al, 2016 , Zhang et al, 2009 , Jung et al, 2008 , Ebato et al, 2008 ).…”