Cell death and inflammatory bowel diseases: Apoptosis, necrosis, and autophagy in the intestinal epithelium

BioMed Research International

Volumn 2014, Issue , 2014, Pages

  Nunes, Tiago ^a   Bernardazzi, Claudio ^b   De Souza, Heitor S ^b,c  

^a TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^b FEDERAL UNIVERSITY OF RIO DE JANEIRO   (Brazil)

^c D OR INSTITUTE FOR RESEARCH AND EDUCATION IDOR   (Brazil)

Author keywords

[No Author keywords available]

Indexed keywords

ADAPTIVE IMMUNITY; AMINO ACID SUBSTITUTION; APOPTOSIS; AUTOPHAGOSOME; AUTOPHAGY; CELL DAMAGE; CELL DEATH; CELL SURVIVAL; CROHN DISEASE; DNA DAMAGE; ENDOPLASMIC RETICULUM STRESS; GENETIC ASSOCIATION; HUMAN; IMMUNOLOGICAL TOLERANCE; INFLAMMATORY BOWEL DISEASE; INNATE IMMUNITY; INTESTINAL STEM CELL; INTESTINE EPITHELIUM; INTESTINE EPITHELIUM CELL; MICROENVIRONMENT; MITOCHONDRIAL PERMEABILITY; NECROPTOSIS; NONHUMAN; PANETH CELL; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; ULCERATIVE COLITIS; ANIMAL; GENETICS; INTESTINE MUCOSA; MOUSE; NECROSIS; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; APOPTOSIS; AUTOPHAGY; HUMANS; INFLAMMATORY BOWEL DISEASES; INTESTINAL MUCOSA; MICE; NECROSIS; SIGNAL TRANSDUCTION;

EID: 84929050802     PISSN: 23146133     EISSN: 23146141     Source Type: Journal    
DOI: 10.1155/2014/218493     Document Type: Review

References (129)

1. C. Nathan, "Points of control in inflammation, " Nature, vol. 420, no. 6917, pp. 846-852, 2002.
2. T. Lawrence and D. W. Gilroy, "Chronic inflammation: a failure of resolution?" International Journal of Experimental Pathology, vol. 88, no. 2, pp. 85-94, 2007.
3. A. Sturm, H. S. P. de Souza, and C. Fiocchi, "Mucosal T cell proliferation and apoptosis in inflammatory bowel disease, " Current Drug Targets, vol. 9, no. 5, pp. 381-387, 2008.
4. A. Strasser and M. Pellegrini, "T-lymphocyte death during shutdown of an immune response, " Trends in Immunology, vol. 25, no. 11, pp. 610-615, 2004.
5. T. Nunes, C. Bernardazzi, and H. S. de Souza, "Interleukin-33 and inflammatory bowel diseases: lessons fromhuman studies, " Mediators of Inflammation, vol. 2014, Article ID 423957, 10 pages, 2014.
6. M. Boirivant, M. Marini, G. Di Felice et al., "Lamina propria T cells in Crohns disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis, " Gastroenterology, vol. 116, no. 3, pp. 557-565, 1999.
7. K. Ina, J. Itoh, K. Fukushima et al., "ResistanceofCrohns disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance, " Journal of Immunology, vol. 163, no. 2, pp. 1081-1090, 1999.
8. J. Itoh, C. de laMotte, S. A. Strong, A. D. Levine, and C. Fiocchi, "Decreased Bax expression bymucosal T cells favours resistance to apoptosis in Crohns disease, " Gut, vol. 49, no. 1, pp. 35-41, 2001.
9. J. M. H. van den Brande, M. P. Peppelenbosch, and S. J. H. van Deventer, "Treating Crohn's disease by inducing T lymphocyte apoptosis, " Annals of the New York Academy of Sciences, vol. 973, pp. 166-180, 2002.
10. J. M. H. van den Brande, T. C. Koehler, Z. Zelinkova et al., "Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohns disease, " Gut, vol. 56, no. 4, pp. 509-517, 2007.
11. P. Eder, L. Lykowska-Szuber, I. Krela-Kazmierczak, K. Stawczyk-Eder, M. Zabel, and K. Linke, "The influence of infliximab and adalimumab on the expression of apoptosisrelated proteins in lamina propria mononuclear cells and enterocytes in Crohns disease-an immunohistochemical study, " Journal of Crohns and Colitis, vol. 7, no. 9, pp. 706-716, 2013.
12. H. S. P. De Souza, G. A. West, N. Rebert, C. De La Motte, J. Drazba, and C. Fiocchi, "Increased levels of survivin, via association with heat shock protein 90, in mucosal T cells from patients with Crohns disease, " Gastroenterology, vol. 143, no. 4, pp. 1017. e9-1026. e9, 2012.
13. T. Nunes, G. Fiorino, S. Danese, and M. Sans, "Familial aggregation in inflammatory bowel disease: is it genes or environment?" World Journal of Gastroenterology, vol. 17, no. 22, pp. 2715-2722, 2011.
14. A. Franke, D. P. McGovern, J. C. Barrett et al., "Genome-wide meta-analysis increases to 71 the number of confirmed Crohns disease susceptibility loci, " Nature Genetics, vol. 42, no. 12, pp. 1118-1125, 2010.
15. C. A. Anderson, G. Boucher, C. W. Lees et al., "Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47, " Nature Genetics, vol. 43, no. 3, pp. 246-252, 2011.
16. L. Jostins, S. Ripke, R. K. Weersma et al., "Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, " Nature, vol. 491, no. 7422, pp. 119-124, 2012.
17. L. Vereecke, R. Beyaert, and G. van Loo, "Enterocyte death and intestinal barrier maintenance in homeostasis and disease, " Trends in Molecular Medicine, vol. 17, no. 10, pp. 584-593, 2011.
18. N. Miron and V. Cristea, "Enterocytes: active cells in tolerance to food and microbial antigens in the gut, " Clinical and Experimental Immunology, vol. 167, no. 3, pp. 405-412, 2012.
19. N. H. Salzman, "Paneth cell defensins and the regulation of the microbiome detente at mucosal surfaces, " Gut Microbes, vol. 1, no. 6, pp. 401-406, 2010.
20. M. Hocker and B. Wiedenmann, "Molecular mechanisms of enteroendocrine differentiation, " Annals of the New York Academy of Sciences, vol. 859, pp. 160-174, 1998.
21. R. D. Specian and M. G. Oliver, "Functional biology of intestinal goblet cells, " American Journal of Physiology: Cell Physiology, vol. 260, no. 2, pp. C183-C193, 1991.
22. C. S. Potten, R. Gandara, Y. R. Mahida, M. Loeffler, and N. A. Wright, "The stem cells of small intestinal crypts: where are they?" Cell Proliferation, vol. 42, no. 6, pp. 731-750, 2009.
23. C. Crosnier, D. Stamataki, and J. Lewis, "Organizing cell renewal in the intestine: stem cells, signals and combinatorial control, " Nature Reviews Genetics, vol. 7, no. 5, pp. 349-359, 2006.
24. K. L. Edelblum, F. Yan, T. Yamaoka, and D. B. Polk, "Regulation of apoptosis during homeostasis and disease in the intestinal epithelium, " Inflammatory BowelDiseases, vol. 12, no. 5, pp. 413-424, 2006.
25. A. di Sabatino, R. Ciccocioppo, O. Luinetti et al., "Increased enterocyte apoptosis in inflamed areas of Crohns disease, " Diseases of the Colon and Rectum, vol. 46, no. 11, pp. 1498-1507, 2003.
26. A. Ramachandran, M. Madesh, and K. A. Balasubramanian, "Apoptosis in the intestinal epithelium: its relevance in normal and pathophysiological conditions, " Journal of Gastroenterology and Hepatology, vol. 15, no. 2, pp. 109-120, 2000.
27. C. O. Souza, G. F. Santoro, V. R. Figliuolo et al., "Extracellular ATP induces cell death in human intestinal epithelial cells, " Biochimica et Biophysica Acta-General Subjects, vol. 1820, no. 12, pp. 1867-1878, 2012.
28. A. R. Neves, M. T. Castelo-Branco, V. R. Figliuolo et al., "Overexpression of ATP-activated P2X7 receptors in the intestinal mucosa is implicated in the pathogenesis of Crohns disease, " Inflammatory Bowel Diseases, vol. 20, no. 3, pp. 444-457, 2014.
29. C. C. Marques, M. T. Castelo-Branco, R. G. Pacheco et al., "Prophylactic systemic P2X7 receptor blockade prevents experimental colitis, " Biochimica et Biophysica Acta, vol. 1842, no. 1, pp. 65-78, 2014.
30. S. Conus and H. U. Simon, "Cathepsins: key modulators of cell death and inflammatory responses, " Biochemical Pharmacology, vol. 76, no. 11, pp. 1374-1382, 2008.
31. H. Malhi, G. J. Gores, and J. J. Lemasters, "Apoptosis and necrosis in the liver: a tale of two deaths?" Hepatology, vol. 43, no. 2, supplement 1, pp. S31-S44, 2006.
32. L. E. Broker, F. A. E. Kruyt, and G. Giaccone, "Cell death independent of caspases: a review, " Clinical Cancer Research, vol. 11, no. 9, pp. 3155-3162, 2005.
33. G. Kroemer, L. Galluzzi, P. Vandenabeele et al., "Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009, " Cell Death and Differentiation, vol. 16, no. 1, pp. 3-11, 2009.
34. V. S. Marsden and A. Strasser, "Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more, " Annual Review of Immunology, vol. 21, pp. 71-105, 2003.
35. A. Strasser, A. W. Harris, D. C. S. Huang, P. H. Krammer, and S. Cory, "Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis, " The EMBO Journal, vol. 14, no. 24, pp. 6136-6147, 1995.
36. K. H. Vousden and X. Lu, "Live or let die: the cell's response to p53, " Nature Reviews Cancer, vol. 2, no. 8, pp. 594-604, 2002.
37. M. Oren, "Decision making by p53: life, death and cancer, " Cell Death and Differentiation, vol. 10, no. 4, pp. 431-442, 2003.
38. E. Oda, R. Ohki, H. Murasawa et al., "Noxa, a BH3-onlymember of the Bcl-2 family and candidate mediator of p53-induced apoptosis, " Science, vol. 288, no. 5468, pp. 1053-1058, 2000.
39. A. S. Gillings, K. Balmanno, C. M. Wiggins, M. Johnson, and S. J. Cook, "Apoptosis and autophagy: BIMas a mediator of tumour cell death in response to oncogene-targeted therapeutics, " FEBS Journal, vol. 276, no. 21, pp. 6050-6062, 2009.
40. J. E. Chipuk, L. Bouchier-Hayes, T. Kuwana, D. D. Newmeyer, and D. R. Green, "Cell biology: PUMA couples the nuclear and cytoplasmic proapoptotic function of p53, " Science, vol. 309, no. 5741, pp. 1732-1735, 2005.
41. H. Kim, M. Rafiuddin-Shah, H. Tu et al., "Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies, " Nature Cell Biology, vol. 8, no. 12, pp. 1348-1358, 2006.
42. T. Kuwana, L. Bouchier-Hayes, J. E. Chipuk et al., "BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly, " Molecular Cell, vol. 17, no. 4, pp. 525-535, 2005.
43. T. F. Bullen, S. Forrest, F. Campbell et al., "Characterization of epithelial cell shedding fromhuman small intestine, " Laboratory Investigation, vol. 86, no. 10, pp. 1052-1063, 2006.
44. A. M. Marchiando, L. Shen, W. V. Graham et al., "The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding, " Gastroenterology, vol. 140, no. 4, pp. 1208-1218, 2011.
45. S. A. Lakhani, A. Masud, K. Kuida et al., "Caspases 3 and 7: key mediators of mitochondrial events of apoptosis, " Science, vol. 311, no. 5762, pp. 847-851, 2006.
46. B. M. Brinkman, F. Hildebrand, M. Kubica et al., "Caspase deficiency alters the murine gut microbiome., " Cell Death and Disease, vol. 2, p. e220, 2011.
47. C. Gunther, E. Martini, N. Wittkopf et al., "Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis, " Nature, vol. 477, no. 7364, pp. 335-339, 2011.
48. P.-S. Welz, A. Wullaert, K. Vlantis et al., "FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation, " Nature, vol. 477, no. 7364, pp. 330-334, 2011.
49. A. G. Renehan, S. P. Bach, and C. S. Potten, "The relevance of apoptosis for cellular homeostasis and tumorigenesis in the intestine, " Canadian Journal of Gastroenterology, vol. 15, no. 3, pp. 166-176, 2001.
50. A. J. Merritt, C. S. Potten, A. J. M. Watson, D. Y. Loh, K. Nakayama, and J. A. Hickman, "Differential expression of bcl-2 in intestinal epithelia: correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia, " Journal of Cell Science, vol. 108, part 6, pp. 2261-2271, 1995.
51. H. S. P. Souza, C. J. A. Tortori, M. T. L. Castelo-Branco et al., "Apoptosis in the intestinal mucosa of patients with inflammatory bowel disease: evidence of altered expression of FasL and perforin cytotoxic pathways, " International Journal of Colorectal Disease, vol. 20, no. 3, pp. 277-286, 2005.
52. M. Iwamoto, T. Koji, K. Makiyama, N. Kobayashi, and P. K. Nakane, "Apoptosis of crypt epithelial cells in ulcerative colitis, " The Journal of Pathology, vol. 180, no. 2, pp. 152-159, 1996.
53. C. Hagiwara, M. Tanaka, and H. Kudo, "Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery, " Journal of Gastroenterology and Hepatology, vol. 17, no. 7, pp. 758-764, 2002.
54. A. Shkoda, T. Werner, H. Daniel, M. Gunckel, G. Rogler, and D. Haller, "Differential protein expression profile in the intestinal epithelium from patients with inflammatory bowel disease, " Journal of Proteome Research, vol. 6, no. 3, pp. 1114-1125, 2007.
55. M. J. Rosen, M. R. Frey, M. K. Washington et al., "STAT6 activation in ulcerative colitis: a new target for prevention of IL-13-induced colon epithelial cell dysfunction, " Inflammatory Bowel Diseases, vol. 17, no. 11, pp. 2224-2234, 2011.
56. F. Heller, P. Florian, C. Bojarski et al., "Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution, " Gastroenterology, vol. 129, no. 2, pp. 550-564, 2005.
57. A. Kaser, A. Lee, A. Franke et al., "XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease, " Cell, vol. 134, no. 5, pp. 743-756, 2008.
58. A. Nenci, C. Becker, A. Wullaert et al., "Epithelial NEMO links innate immunity to chronic intestinal inflammation, " Nature, vol. 446, no. 7135, pp. 557-561, 2007.
59. K. A. Steinbrecher, E. Harmel-Laws, R. Sitcheran, and A. S. Baldwin, "Loss of epithelial RelA results in deregulated intestinal proliferative/apoptotic homeostasis and susceptibility to inflammation, " Journal of Immunology, vol. 180, no. 4, pp. 2588-2599, 2008.
60. G. Pickert, C. Neufert, M. Leppkes et al., "STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing, " Journal of Experimental Medicine, vol. 206, no. 7, pp. 1465-1472, 2009.
61. T. Werner, S. J. Wagner, I. Martinez et al., "Depletion of luminal iron alters the gut microbiota and prevents Crohns disease-like ileitis, " Gut, vol. 60, no. 3, pp. 325-333, 2011.
62. D. F. Mccole, L. Eckmann, F. Laurent, and M. F. Kagnoff, "Intestinal epithelial cell apoptosis following Cryptosporidium parrum infection, " Infection and Immunity, vol. 68, no. 3, pp. 1710-1713, 2000.
63. S. E. Winter and A. J. Baumler, "Salmonella exploits suicidal behavior of epithelial cells, " Frontiers in Microbiology, vol. 2, article 48, 2011.
64. L. A. Knodler, B. A. Vallance, J. Celli et al., "Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia, " Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 41, pp. 17733-17738, 2010.
65. T. Fernandes-Alnemri, J. Wu, J.-W. Yu et al., "The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation, " Cell Death and Differentiation, vol. 14, no. 9, pp. 1590-1604, 2007.
66. A. Rubartelli and M. T. Lotze, "Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox, " Trends in Immunology, vol. 28, no. 10, pp. 429-436, 2007.
67. S. Mariathasan, D. S. Weiss, K. Newton et al., "Cryopyrin activates the inflammasome in response to toxins and ATP, " Nature, vol. 440, no. 7081, pp. 228-232, 2006.
68. P. Pelegrin and A. Surprenant, "Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor, " EMBO Journal, vol. 25, no. 21, pp. 5071-5082, 2006.
69. L. Chen and C. F. Brosnan, "Regulation of immune response by P2X7 receptor, " Critical Reviews in Immunology, vol. 26, no. 6, pp. 499-513, 2006.
70. T. Hlavaty, M. Pierik, L. Henckaerts et al., "Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohns disease, " Alimentary Pharmacology and Therapeutics, vol. 22, no. 7, pp. 613-626, 2005.
71. S. Zeissig, C. Bojarski, N. Buergel et al., "Downregulation of epithelial apoptosis and barrier repair in active Crohns disease by tumour necrosis factor α antibody treatment, " Gut, vol. 53, no. 9, pp. 1295-1302, 2004.
72. M. Marini, G. Bamias, J. Rivera-Nieves et al., "TNF-α neutralization ameliorates the severity ofmurine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis, " Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 14, pp. 8366-8371, 2003.
73. G. Majno and I. Joris, "Apoptosis, oncosis, and necrosis: an overview of cell death, " American Journal of Pathology, vol. 146, no. 1, pp. 3-15, 1995.
74. M. Los, M. Mozoluk, D. Ferrari et al., "Activation and caspasemediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling, " Molecular Biology of the Cell, vol. 13, no. 3, pp. 978-988, 2002.
75. N. Vanlangenakker, T. VandenBerghe, D. V. Krysko, N. Festjens, and P. Vandenabeele, "Molecular mechanisms and pathophysiology of necrotic cell death, " Current Molecular Medicine, vol. 8, no. 3, pp. 207-220, 2008.
76. M. Francois, V. Le Cabec, M. Dupont, P. J. Sansonetti, and I. Maridonneau-Parini, "Induction of necrosis in human neutrophils by Shigella flexneri requires type III secretion, IpaB and IpaC invasins, and actin polymerization, " Infection and Immunity, vol. 68, no. 3, pp. 1289-1296, 2000.
77. P. Golstein and G. Kroemer, "Cell death by necrosis: towards a molecular definition, " Trends in Biochemical Sciences, vol. 32, no. 1, pp. 37-43, 2007.
78. D. Vercammen, R. Beyaert, G. Denecker et al., "Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor, "The Journal of Experimental Medicine, vol. 187, no. 9, pp. 1477-1485, 1998.
79. S. M. Laster, J. G. Wood, and L. R. Gooding, "Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis, " The Journal of Immunology, vol. 141, no. 8, pp. 2629-2634, 1988.
80. D. Vercammen, R. Beyaert, G. Denecker et al., "Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor, " Journal of Experimental Medicine, vol. 187, no. 9, pp. 1477-1485, 1998.
81. N. Holler, R. Zaru, O. Micheau et al., "Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effectormolecule, " Nature Immunology, vol. 1, no. 6, pp. 489-495, 2000.
82. A. Kawahara, Y. Ohsawa, H. Matsumura, Y. Uchiyama, and S. Nagata, "Caspase-independent cell killing by Fas-associated protein with death domain, "The Journal of Cell Biology, vol. 143, no. 5, pp. 1353-1360, 1998.
83. W. Wu, P. Liu, and J. Li, "Necroptosis: an emerging formof programmed cell death, " Critical Reviews in Oncology/Hematology, vol. 82, no. 3, pp. 249-258, 2012.
84. C. Giampietri, D. Starace, S. Petrungaro, A. Filippini, and E. Ziparo, "Necroptosis: molecular signalling and translational implications, " International Journal of Cell Biology, vol. 2014, Article ID 490275, 6 pages, 2014.
85. A. J. M. Watson, "Necrosis and apoptosis in the gastrointestinal tract, " Gut, vol. 37, no. 2, pp. 165-167, 1995.
86. R. R. Dourmashkin, H. Davies, C. Wells et al., "Epithelial patchy necrosis in Crohns disease, " Human Pathology, vol. 14, no. 7, pp. 643-648, 1983.
87. E. Watanabe, J. T. Muenzer, W. G. Hawkins et al., "Sepsis induces extensive autophagic vacuolization in hepatocytes: a clinical and laboratory-based study, " Laboratory Investigation, vol. 89, no. 5, pp. 549-561, 2009.
88. B. Levine and V. Deretic, "Unveiling the roles of autophagy in innate and adaptive immunity, " Nature Reviews Immunology, vol. 7, no. 10, pp. 767-777, 2007.
89. W. Bursch, "The autophagosomal-lysosomal compartment in programmed cell death, " Cell Death and Differentiation, vol. 8, no. 6, pp. 569-581, 2001.
90. G. Kroemer and M. Jaattela, "Lysosomes and autophagy in cell death control, " Nature Reviews Cancer, vol. 5, no. 11, pp. 886-897, 2005.
91. S. F. Funderburk, Q. J. Wang, and Z. Yue, "The Beclin 1-VPS34 complex -at the crossroads of autophagy and beyond, " Trends in Cell Biology, vol. 20, no. 6, pp. 355-362, 2010.
92. J. Kubisch, D. Turei, L. Foldvari-Nagy et al., "Complex regulation of autophagy in cancer-integrated approaches to discover the networks that hold a double-edged sword, " Seminars in Cancer Biology, vol. 23, no. 4, pp. 252-261, 2013.
93. J. Goldsmith, B. Levine, and J. Debnath, "Autophagy and cancer metabolism, " Methods in Enzymology, vol. 542, pp. 25-57, 2014.
94. J. Hampe, A. Franke, P. Rosenstiel et al., "A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1, " Nature Genetics, vol. 39, no. 2, pp. 207-211, 2007.
95. N. J. Prescott, S. A. Fisher, A. Franke et al., "A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5, " Gastroenterology, vol. 132, no. 5, pp. 1665-1671, 2007.
96. A. Kabi, K. P. Nickerson, C. R. Homer, and C. McDonald, "Digesting the genetics of inflammatory bowel disease: insights from studies of autophagy risk genes, " Inflammatory Bowel Diseases, vol. 18, no. 4, pp. 782-792, 2012.
97. J. van Limbergen, R. K. Russell, E. R. Nimmo et al., "Autophagy gene ATG16L1 influences susceptibility and disease location but not childhood-onset in Crohns disease in northern Europe, " Inflammatory Bowel Diseases, vol. 14, no. 3, pp. 338-346, 2008.
98. J. R. F. Cummings, R. Cooney, S. Pathan et al., "Confirmation of the role of ATG16L1 as a Crohns disease susceptibility gene, " Inflammatory Bowel Diseases, vol. 13, no. 8, pp. 941-946, 2007.
99. T. Saitoh, N. Fujita, M. H. Jang et al., "Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production, " Nature, vol. 456, no. 7219, pp. 264-268, 2008.
100. K. Cadwell, J. Y. Liu, S. L. Brown et al., "Akey role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells, " Nature, vol. 456, no. 7219, pp. 259-263, 2008.
101. K. Cadwell, K. K. Patel, N. S. Maloney et al., "Virus-plussusceptibility gene interaction determines Crohns disease gene Atg16L1 phenotypes in intestine, " Cell, vol. 141, no. 7, pp. 1135-1145, 2010.
102. R. Cooney, J. Baker, O. Brain et al., "NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation, " Nature Medicine, vol. 16, no. 1, pp. 90-97, 2010.
103. M. T. Sorbara, L. K. Ellison, M. Ramjeet et al., "The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagyindependent manner, " Immunity, vol. 39, no. 5, pp. 858-873, 2013.
104. N. Fujita, T. Saitoh, S. Kageyama, S. Akira, T. Noda, and T. Yoshimori, "Differential involvement of Atg16L1 in Crohn disease and canonical autophagy: Analysis of the organization of the Atg16L1 complex in fibroblasts, " The Journal of Biological Chemistry, vol. 284, no. 47, pp. 32602-32609, 2009.
105. J. S. Messer, S. F. Murphy, M. F. Logsdon et al., "The Crohn's disease: associated ATG16L1 variant and Salmonella invasion, " BMJ Open, vol. 3, no. 6, Article ID e002790, 2013.
106. K. L. Conway, P. Kuballa, J. H. Song et al., "Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection, " Gastroenterology, vol. 145, no. 6, pp. 1347-1357, 2013.
107. P. Lapaquette, A.-L. Glasser, A. Huett, R. J. Xavier, and A. Darfeuille-Michaud, "Crohns disease-associated adherentinvasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly, " Cellular Microbiology, vol. 12, no. 1, pp. 99-113, 2010.
108. A. Murthy, Y. Li, I. Peng et al., "A Crohns disease variant in Atg16l1 enhances its degradation by caspase 3, " Nature, vol. 506, no. 7489, pp. 456-462, 2014.
109. T. E. Adolph, M. F. Tomczak, L. Niederreiter et al., "Paneth cells as a site of origin for intestinal inflammation, " Nature, vol. 503, no. 7475, pp. 272-276, 2013.
110. J. J. Deuring, G. M. Fuhler, S. R. Konstantinov et al., "Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohns disease, " Gut, vol. 63, no. 7, pp. 1081-1091, 2013.
111. R. J. Palomino-Morales, J. Oliver, M. Gomez-Garcia et al., "Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach, " Genes and Immunity, vol. 10, no. 4, pp. 356-364, 2009.
112. S. B. Singh, A. S. Davis, G. A. Taylor, and V. Deretic, "Human IRGMinduces autophagy to eliminate intracellularmycobacteria, " Science, vol. 313, no. 5792, pp. 1438-1441, 2006.
113. H. T. T. Nguyen, P. Lapaquette, M. Bringer, and A. Darfeuille-Michaud, "Autophagy and crohns disease, " Journal of Innate Immunity, vol. 5, no. 5, pp. 434-443, 2013.
114. S. A. McCarroll, A. Huett, P. Kuballa et al., "Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohns disease, " Nature Genetics, vol. 40, no. 9, pp. 1107-1112, 2008.
115. M. Parkes, J. C. Barrett, N. J. Prescott et al., "Sequence variants in the autophagy gene IRGMandmultiple other replicating loci contribute to Crohns disease susceptibility, " Nature Genetics, vol. 39, no. 7, pp. 830-832, 2007.
116. P. Brest, P. Lapaquette, B. Mograbi, A. Darfeuille-Michaud, and P. Hofman, "Risk predisposition for Crohn disease: a "menage a trois" combining IRGM allele, miRNA and xenophagy, " Autophagy, vol. 7, no. 7, pp. 786-787, 2011.
117. P. Brest, P. Lapaquette, M. Souidi et al., "A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy inCrohn's disease, " Nature Genetics, vol. 43, no. 3, pp. 242-245, 2011.
118. M. Georges, "The long and winding road from correlation to causation, " Nature Genetics, vol. 43, no. 3, pp. 180-181, 2011.
119. J. Glas, J. Seiderer, S. Bues et al., "IRGMvariants and susceptibility to inflammatory bowel disease in the German population, " PLoS ONE, vol. 8, no. 1, Article ID e54338, 2013.
120. A. Latiano, O. Palmieri, S. Cucchiara et al., "Polymorphism of the IRGM gene might predispose to fistulizing behavior in crohns disease, " American Journal of Gastroenterology, vol. 104, no. 1, pp. 110-116, 2009.
121. R. L. Roberts, J. E. Hollis-Moffatt, R. B. Gearry, M. A. Kennedy, M. L. Barclay, and T. R. Merriman, "Confirmation of association of IRGM and NCF4 with ileal Crohns disease in a populationbased cohort, " Genes and Immunity, vol. 9, no. 6, pp. 561-565, 2008.
122. C. Duraes, J. C. Machado, F. Portela et al., "Phenotype-genotype profiles in Crohns disease predicted by genetic markers in autophagy-related genes (GOIA study II), " Inflammatory Bowel Diseases, vol. 19, no. 2, pp. 230-239, 2013.
123. R. Sehgal, A. Berg, J. I. Polinski et al., "Mutations in IRGM are associated withmore frequent need for surgery in patients with ileocolonic crohns disease, " Diseases of the Colon and Rectum, vol. 55, no. 2, pp. 115-121, 2012.
124. T. B. Murdoch, W. Xu, J. M. Stempak et al., "Pattern recognition receptor and autophagy gene variants are associated with development of antimicrobial antibodies in Crohns disease, " Inflammatory Bowel Diseases, vol. 18, no. 9, pp. 1743-1748, 2012.
125. V. Nikoletopoulou, M. Markaki, K. Palikaras, and N. Tavernarakis, "Crosstalk between apoptosis, necrosis and autophagy, " Biochimica et Biophysica Acta, vol. 1833, no. 12, pp. 3448-3459, 2013.
126. M. V. Jain, A. M. Paczulla, T. Klonisch et al., "Interconnections between apoptotic, autophagic and necrotic pathways: implications for cancer therapy development, " Journal of Cellular and Molecular Medicine, vol. 17, no. 1, pp. 12-29, 2013.
127. A. D. Rubinstein and A. Kimchi, "Life in the balance-a mechanistic view of the crosstalk between autophagy and apoptosis, " Journal of Cell Science, vol. 125, part 22, pp. 5259-5268, 2012.
128. K. M. Irrinki, K. Mallilankaraman, R. J. Thapa et al., "Requirement of FADD, NEMO, and BAX/BAK for aberrant mitochondrial function in tumor necrosis factor α-induced necrosis, " Molecular and Cellular Biology, vol. 31, no. 18, pp. 3745-3758, 2011.
129. W. Ding, H. Ni, W. Gao et al., "Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival, " The Journal of Biological Chemistry, vol. 282, no. 7, pp. 4702-4710, 2007