Paneth cells as a site of origin for intestinal inflammation

被引:556
作者
Adolph, Timon E. [1 ]
Tomczak, Michal F. [2 ]
Niederreiter, Lukas [1 ]
Ko, Hyun-Jeong [2 ]
Boeck, Janne [3 ]
Martinez-Naves, Eduardo [4 ]
Glickman, Jonathan N. [5 ]
Tschurtschenthaler, Markus [1 ,6 ]
Hartwig, John [7 ]
Hosomi, Shuhei [2 ]
Flak, Magdalena B. [2 ]
Cusick, Jennifer L. [2 ]
Kohno, Kenji [8 ]
Iwawaki, Takao [9 ,10 ]
Billmann-Born, Susanne [3 ]
Raine, Tim [1 ]
Bharti, Richa [3 ]
Lucius, Ralph [11 ]
Kweon, Mi-Na [12 ]
Marciniak, Stefan J. [13 ]
Choi, Augustine [14 ]
Hagen, Susan J. [15 ]
Schreiber, Stefan [3 ]
Rosenstiel, Philip [3 ]
Kaser, Arthur [1 ]
Blumberg, Richard S. [2 ]
机构
[1] Univ Cambridge, Addenbrookes Hosp, Dept Med, Div Gastroenterol & Hepatol, Cambridge CB2 0QQ, England
[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol,Dept Med, Boston, MA 02115 USA
[3] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany
[4] Univ Complutense Madrid, Fac Med, Dept Microbiol & Immunol, E-28040 Madrid, Spain
[5] Miraca Life Sci, GI Pathol Div, Newton, MA 02464 USA
[6] Med Univ Innsbruck, Dept Med, A-6020 Innsbruck, Austria
[7] Harvard Univ, Brigham & Womens Hosp, Sch Med, Translat Med Div,Dept Med, Boston, MA 02115 USA
[8] Nara Inst Sci & Technol NAIST, Grad Sch Biol Sci, Lab Mol & Cell Genet, Nara 6300192, Japan
[9] Gunma Univ, Adv Sci Res Leaders Dev Unit, Maebashi, Gunma 3718511, Japan
[10] RIKEN, Adv Sci Inst, Iwawaki Initiat Res Unit, Wako, Saitama 3510198, Japan
[11] Univ Kiel, Anat Inst, D-24098 Kiel, Germany
[12] Int Vaccine Inst, Div Sci Lab, Mucosal Immunol Sect, Seoul 151818, South Korea
[13] Univ Cambridge, Dept Med, Cambridge Inst Med Res CIMR, Cambridge CB2 0XY, England
[14] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pulm & Crit Care Med,Dept Med, Boston, MA 02115 USA
[15] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA
基金
新加坡国家研究基金会; 欧洲研究理事会; 奥地利科学基金会;
关键词
ENDOPLASMIC-RETICULUM STRESS; GENOME-WIDE ASSOCIATION; FACTOR-KAPPA-B; ER STRESS; SUSCEPTIBILITY LOCI; EPITHELIAL-CELLS; CROHN-DISEASE; GENE ATG16L1; AUTOPHAGY; ACTIVATION;
D O I
10.1038/nature12599
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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(1). Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction(2,3). As Atg16l1(HM) 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 epithelium(4,5), and several genetic risk factors of Crohn's disease affect Paneth cells(2,4,6-9). Here we show that impairment in either UPR (Xbp1(Delta IEC)) or autophagy function (Atg16l1(Delta IEC) or Atg7(Delta IEC)) 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. Xbp1DIEC 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 2 alpha (eIF2 alpha) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1 alpha (IRE1 alpha)-regulated NF-kappa B activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1a activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-kappa B 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.
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页码:272 / +
页数:22
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