Paneth cells as a site of origin for intestinal inflammation
By Timon E. Adolph, Michal Tomczak, L. Niederreiter, Hyun-Jeong Ko, Janne Böck, E. Martínez-Naves, J. Glickman, Markus Tschurtschenthaler, J. Hartwig, S. Hosomi and 16 more. Nature, 2013
696 citations recorded by the source corpus.
The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn’s disease. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1HM mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn’s disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1ΔIEC) or autophagy function (Atg16l1ΔIEC or Atg7ΔIEC) in intestinal epithelial cells results in each other’s compensatory engagement, and severe spontaneous Crohn’s-disease-like transmural ileitis if both mechanisms are compromised. Xbp1ΔIEC mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn’s disease as a specific disorder of Paneth cells.
Subfields: Cell Biology, Epidemiology, Surgery
View Paper: https://www.semanticscholar.org/paper/26799b08c2844a6e528c10c151800ed0946b9e89
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Cell Biology
In Epidemiology
In Surgery
Citations in the corpus
- GENETICS AND PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE (2016, background): “Atg16L1 function is required to counteract effects of loss of the unfolded protein response and to inhibit inflammation (64).”
- The gut microbiota and inflammatory bowel disease (2014, positive): “Mice deficient in Xbp1 , which is an essential molecule for endoplasmic reticulum stress and is a CD susceptibility gene, also have impaired autophagy induction in Paneth cells and develop spontaneous ileitis [44].”
- New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD (2019, background): “Abbreviations: AIEC: adherent-invasive Escherichia coli; AMPK: AMP-activated protein kinase; ATF6: activating transcription factor 6; ATG: autophagy related; Atg16l1[ΔIEC] mice: mice with Atg16l1 depletion specifically in intestinal epithelial cells; Atg16l1[HM] mice: mice hypomorphic for Atg16l1 ex”
- Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, positive): “mouse models of intestinal inflammation driven by ER-stress exhibit strong LC3 puncta staining.(391,392) In various neurodegenerative states, LC3 puncta may be numerous in neurites,”