Paneth cells as a site of origin for intestinal inflammation.

Adolph, T. E., Tomczak, M. F., Niederreiter, L., Ko, H. J., Bock, J., Martinez-Naves, E., Glickman, J. N., Tschurtschenthaler, M., Hartwig, J., Hosomi, S., Flak, M. B., Cusick, J. L., Kohno, K., Iwawaki, T., Billmann-Born, S., Raine, T., Bharti, R., Lucius, R., Kweon, M. N., Marciniak, S. J., Choi, A., Hagen, S. J., Schreiber, Stefan, Rosenstiel, P., Kaser, A. and Blumberg, R. S. (2013) Paneth cells as a site of origin for intestinal inflammation. Nature, 503 (7475). 272-+. DOI 10.1038/nature12599.

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Supplementary data:

Abstract

The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn’s disease1. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction2,3. 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 enteritis4. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium4,5, and several genetic risk factors of Crohn’s disease affect Paneth cells2,4,6,7,8,9. 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.

Document Type: Article
Additional Information: Times Cited: 5 Adolph, Timon E. Tomczak, Michal F. Niederreiter, Lukas Ko, Hyun-Jeong Boeck, Janne Martinez-Naves, Eduardo Glickman, Jonathan N. Tschurtschenthaler, Markus Hartwig, John Hosomi, Shuhei Flak, Magdalena B. Cusick, Jennifer L. Kohno, Kenji Iwawaki, Takao Billmann-Born, Susanne Raine, Tim Bharti, Richa Lucius, Ralph Kweon, Mi-Na Marciniak, Stefan J. Choi, Augustine Hagen, Susan J. Schreiber, Stefan Rosenstiel, Philip Kaser, Arthur Blumberg, Richard S.
Keywords: Immunology, Inflammatory bowel disease
Research affiliation: OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
Open Access Journal?: No
DOI etc.: 10.1038/nature12599
ISSN: 0028-0836
Projects: Future Ocean
Date Deposited: 08 Jul 2014 08:48
Last Modified: 15 Jul 2019 09:15
URI: http://oceanrep.geomar.de/id/eprint/24798

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