Role of autophagy and autophagy genes in inflammatory bowel disease

Current Topics in Microbiology and Immunology

Volumn 335, Issue 1, 2009, Pages 141-167

  Cadwell, Ken ^a   Stappenbeck, Thaddeus S ^a   Virgin, Herbert W ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CASPASE RECRUITMENT DOMAIN PROTEIN 15; DEXTRAN SULFATE; INTERLEUKIN 1BETA; TRANSFORMING GROWTH FACTOR BETA RECEPTOR; TUMOR NECROSIS FACTOR ALPHA; X BOX BINDING PROTEIN 1; ATG16L1 PROTEIN, HUMAN; CARRIER PROTEIN; GUANINE NUCLEOTIDE BINDING PROTEIN; IRGM PROTEIN, HUMAN;

ATG16L1 GENE; AUTOPHAGY; BACTERIAL COLONIZATION; CLOSTRIDIUM DIFFICILE; CROHN DISEASE; CYTOKINE RELEASE; DISEASE MODEL; GENE; GENE DELETION; GENE FUNCTION; GENE IDENTIFICATION; GENE OVEREXPRESSION; GENETIC ANALYSIS; GENETIC SUSCEPTIBILITY; HOST PATHOGEN INTERACTION; IN VIVO STUDY; INFLAMMATION; IRGM1 GENE; MACROPHAGE ACTIVATION; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; ULCERATIVE COLITIS; ANIMAL; BACTERIUM; ENTERITIS; GENETIC PREDISPOSITION; GENETICS; HUMAN; IMMUNOLOGY; MICROBIOLOGY; MOUSE;

ANIMALS; AUTOPHAGY; BACTERIA; CARRIER PROTEINS; GENETIC PREDISPOSITION TO DISEASE; GTP-BINDING PROTEINS; HUMANS; INFLAMMATORY BOWEL DISEASES; MICE;

EID: 75649108606     PISSN: 0070217X     EISSN: None     Source Type: Book Series    
DOI: 10.1007/978-3-642-00302-8_7     Document Type: Review

References (100)

1. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y, Dynlacht BD (2007) XBP1 controls diverse cell type-and condition-specific transcriptional regulatory networks. Mol Cell 27:53-66
2. Ahmad T, Armuzzi A, Bunce M, Mulcahy-Hawes K, Marshall SE, Orchard TR, Crawshaw J, Large O, de SA, Cook JT, Barnardo M, Cullen S, Welsh KI, Jewell DP (2002) The molecular classification of the clinical manifestations of Crohn's disease. Gastro 122:854-866
3. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, Griffiths G, Ktistakis NT (2008) Autophagosome formation from membrane compartments enriched in phosphati-dylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182:685-701
4. Barbier M, Vidal H, Desreumaux P, Dubuquoy L, Bourreille A, Colombel JF, Cherbut C, Galmiche JP (2003) Overexpression of leptin mRNA in mesenteric adipose tissue in inflammatory bowel diseases. Gastroenterol Clin Biol 27:987-991
5. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van GA, Zelenika D, Franchimont D, Hugot JP, de VM, Vermeire S, Louis E, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM,Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40:955-962
6. Bastide P, Darido C, Pannequin J, Kist R, Robine S, Marty-Double C, Bibeau F, Scherer G, Joubert D, Hollande F, Blache P, Jay P (2007) Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium 1. J Cell Biol 178:635-648
7. Bekpen C, Hunn JP, Rohde C, Parvanova I, Guethlein L, Dunn DM, Glowalla E, Leptin M, Howard JC (2005) The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome Biol 6:R92
8. Blichfeldt P, Blomhoff JP, Myhre E, Gjone E (1978) Metronidazole in Crohn's disease. A double blind cross-over clinical trial. Scand J Gastroenterol 13:123-127
9. Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J, Elledge SJ (2008) Identification of host proteins required for HIV infection through a functional genomic screen. Science 319:921-926
10. Bry L, Falk P, Huttner K, Ouellette A, Midtvedt T, Gordon JI (1994) Paneth cell differentiation in the developing intestine of normal and transgenic mice. Proc Natl Acad Sci USA 91:10335-10339
11. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, Kishi C, Kc W, Carrero JA, Hunt S, Stone CD, Brunt EM, Xavier RJ, Sleckman BP, Li E, Mizushima N, Stappenbeck TS, Virgin HW (2008a) A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456:259-263
12. Cadwell K, Patel KK, Komatsu M, Virgin HW 4th, Stappenbeck TS (2009) A common role for Atg16L1, Atg5 and Atg7 in small intestinal Paneth cells and Crohn disease. Autophagy 5(2): 250-252.
13. Cho JH (2008) The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8:458-466
14. Delgado MA, Elmaoued RA, Davis AS, Kyei G, Deretic V (2008) Toll-like receptors control autophagy. EMBO J 27:1110-1121
15. Deretic V (2006) Autophagy as an immune defense mechanism. Curr Opin Immunol 18:375-382
16. + T cell populations by preventing interferon-gamma-induced cell death. Nat Immunol 9:1279-1287
17. Ferguson LR, Shelling AN, Browning BL, Huebner C, Petermann I (2007) Genes, diet and inflammatory bowel disease. Mutat Res 622:70-83
18. Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P, Mathew CG, Parkes M, Satsangi J (2008) Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet 40:710-712
19. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR (1993) An essential role for inter-feron gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 178:2249-2254
20. Fujita N, Itoh T, Fukuda M, Noda T, Yoshimori T (2008) The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19:2092-2100
21. Girardin SE, Travassos LH, Herve M, Blanot D, Boneca IG, Philpott DJ, Sansonetti PJ, Mengin-Lecreulx D (2003) Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J Biol Chem 278:41702-41708
22. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected mac-rophages. Cell 119:753-766
23. Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, Macpherson AJ, Bridger S, van DS, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG (2001) Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357:1925-1928
24. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J, Gunther S, Prescott NJ, Onnie CM, Hasler R, Sipos B, Folsch UR, Lengauer T, Platzer M, Mathew CG, Krawczak M, Schreiber S (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39:207-211
25. Heilpern D, Szilagyi A (2008) Manipulation of intestinal microbial flora for therapeutic benefit in inflammatory bowel diseases: review of clinical trials of probiotics, pre-biotics and synbiotics. Rev Recent Clin Trials 3:167-184
26. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411:599-603
27. Inbal B, Bialik S, Sabanay I, Shani G, Kimchi A (2002) DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J Cell Biol 157:455-468
28. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M, Foster SJ, Moran AP, Fernandez-Luna JL, Nunez G (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem 278:5509-5512
29. Itoh T, Fujita N, Kanno E, Yamamoto A, Yoshimori T, Fukuda M (2008) Golgi-resident small GTPase Rab33B interacts with Atg16L and modulates autophagosome formation. Mol Biol Cell 19:2916-2925
30. Ivanov II, Frutos RL, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4:337-349
31. Jess T, Riis L, Jespersgaard C, Hougs L, Andersen PS, Orholm MK, Binder V, Munkholm P (2005) Disease concordance, zygosity, and NOD2/CARD15 status: follow-up of a population-based cohort of Danish twins with inflammatory bowel disease. Am J Gastroenterol 100:2486-2492
32. Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ, Ishii KJ, Kawai T, Akira S, Suzuki K, Okuda K (2007) The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci USA 104:14050-14055
33. Kang SS, Bloom SM, Norian LA, Geske MJ, Flavell RA, Stappenbeck TS, Allen PM (2008) An antibiotic-responsive mouse model of fulminant ulcerative colitis. PLoS Med 5:e41
34. Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134:743-756
35. Kitajima S, Takuma S, Morimoto M (1999) Changes in colonic mucosal permeability in mouse colitis induced with dextran sulfate sodium. Exp Anim 48:137-143
36. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307:731-734
37. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169:425-434
38. Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:387-398
39. Kosiewicz MM, Nast CC, Krishnan A, Rivera-Nieves J, Moskaluk CA, Matsumoto S, Kozaiwa K, Cominelli F (2001) Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease. J Clin Invest 107:695-702
40. Kozuch PL, Hanauer SB (2008) Treatment of inflammatory bowel disease: a review of medicaltherapy. World J Gastroenterol 14:354-377
41. Kuballa P, Huett A, Rioux JD, Daly MJ, Xavier RJ (2008) Impaired autophagy of an intracellularpathogen induced by a Crohn's disease associated ATG16L1 variant. PLoS ONE 3:e3391
42. Kuma A, Mizushima N, Ishihara N, Ohsumi Y (2002) Formation of the approximately 350-kDaApg12-Apg5. Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential forautophagy in yeast. J Biol Chem 277:18619-18625
43. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T,Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature432:1032-1036
44. Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, Ogunbiyi O, Nunez G, Keshav S(2003) Crohn's disease and the NOD2 gene: a role for paneth cells. Gastro 125:47-57
45. Leber JH, Crimmins GT, Raghavan S, Meyer-Morse NP, Cox JS, Portnoy DA (2008) DistinctTLR-and NLR-mediated transcriptional responses to an intracellular pathogen. PLoS Pathog4:e6
46. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A (2007) Autophagy-dependent viralrecognition by plasmacytoid dendritic cells. Science 315:1398-1401
47. Levine B, Deretic V (2007) Unveiling the roles of autophagy in innate and adaptive immunity. NatRev Immunol 7:767-777
48. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27-42
49. Lupp C, Robertson ML, Wickham ME, Sekirov I, Champion OL, Gaynor EC, Finlay BB (2007)Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowthof Enterobacteriaceae. Cell Host Microbe 2:204
50. Madison BB, Dunbar L, Qiao XT, Braunstein K, Braunstein E, Gumucio DL (2002) Cis elementsof the villin gene control expression in restricted domains of the vertical (crypt) and horizontal(duodenum, cecum) axes of the intestine. J Biol Chem 277:33275-33283
51. Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, Eckmann L, Karin M (2005)Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing. Science 307:734-738
52. Matsumoto S, Okabe Y, Setoyama H, Takayama K, Ohtsuka J, Funahashi H, Imaoka A, Okada Y,Umesaki Y (1998) Inflammatory bowel disease-like enteritis and caecitis in a senescenceaccelerated mouse P1/Yit strain. Gut 43:71-78
53. Matsushita M, Suzuki NN, Obara K, Fujioka Y, Ohsumi Y, Inagaki F (2007) Structure of Atg5. Atg16, a complex essential for autophagy. J Biol Chem 282:6763-6772
54. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An immunomodulatory molecule ofsymbiotic bacteria directs maturation of the host immune system. Cell 122:107-118
55. Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinalinflammatory disease. Nature 453:620-625
56. McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P, Zody MC, Hall JL, BrantSR, Cho JH, Duerr RH, Silverberg MS, Taylor KD, Rioux JD, Altshuler D, Daly MJ, XavierRJ (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet 40:1107-1112
57. McKenna P, Hoffmann C, Minkah N, Aye PP, Lackner A, Liu Z, Lozupone CA, Hamady M,Knight R, Bushman FD (2008) The macaque gut microbiome in health, lentiviral infection,and chronic enterocolitis. PLoS Pathog 4:e20
58. Mizushima N, Noda T, Ohsumi Y (1999) Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J 18:3888-3896
59. Mizushima N, Kuma A, Kobayashi Y, Yamamoto A, Matsubae M, Takao T, Natsume T, OhsumiY, Yoshimori T (2003) Mouse Apg16L, a novel WD-repeat protein, targets to the autophagicisolation membrane with the Apg12-Apg5 conjugate. J Cell Sci 116:1679-1688
60. Neuman MG (2007) Immune dysfunction in inflammatory bowel disease. Transl Res149:173-186
61. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T,Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB,Nunez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411:603-606
62. Ogura Y, Lala S, Xin W, Smith E, Dowds TA, Chen FF, Zimmermann E, Tretiakova M, Cho JH, Hart J, Greenson JK, Keshav S, Nunez G (2003) Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis. Gut 52:1591-1597
63. Ouellette AJ (2006) Paneth cell alpha-defensin synthesis and function. Curr Top Microbiol Immunol 306:1-25
64. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D, Drummond H, Lees CW, Khawaja SA, Bagnall R, Burke DA, Todhunter CE, Ahmad T, Onnie CM, McArdle W, Strachan D, Bethel G, Bryan C, Lewis CM, Deloukas P, Forbes A, Sanderson J, Jewell DP, Satsangi J, Mansfield JC, Cardon L, Mathew CG (2007) Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 39:830-832
65. Pauleau AL, Murray PJ (2003) Role of nod2 in the response of macrophages to Toll-like receptor agonists. Mol Cell Biol 23:7531-7539
66. Pineton de CG, Colombel JF, Poulain D, rfeuille-Michaud A (2008) Pathogenic agents in inflammatory bowel diseases. Curr Opin Gastroenterol 24:440-447
67. Porter EM, Bevins CL, Ghosh D, Ganz T (2002) The multifaceted Paneth cell. Cell Mol Life Sci 59:156-170
68. Prescott NJ, Fisher SA, Franke A, Hampe J, Onnie CM, Soars D, Bagnall R, Mirza MM, Sanderson J, Forbes A, Mansfield JC, Lewis CM, Schreiber S, Mathew CG (2007) A nonsyn-onymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5. Gastro 132:1665-1671
69. Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI, Woo HN, Cho DH, Choi B, Lee H, Kim JH, Mizushima N, Oshumi Y, Jung YK (2005) Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 280:20722-20729
70. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229-241
71. Rawls JF, Mahowald MA, Ley RE, Gordon JI (2006) Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell 127:423-433
72. Reggiori F, Klionsky DJ (2005) Autophagosomes: biogenesis from scratch? Curr Opin Cell Biol 17:415-422
73. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, Green T, Kuballa P, Barmada MM, Datta LW, Shugart YY, Griffiths AM, Targan SR, Ippoliti AF, Bernard EJ, Mei L, Nicolae DL, Regueiro M, Schumm LP, Steinhart AH, Rotter JI, Duerr RH, Cho JH, Daly MJ, Brant SR (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39:596-604
74. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456:264-268
75. Sandborn WJ Feagan BG (2003) Review article: mild to moderate Crohn's disease\-defining the basis for a new treatment algorithm. Aliment Pharmacol Ther 18:263-277
76. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, Komatsu M, Tanaka K, Cleveland JL, Withoff S, Green DR (2007) Toll-like receptor signaling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253-1257
77. Schaffler A, Herfarth H (2005) Creeping fat in Crohn's disease: travelling in a creeper lane of research?. Gut 54:742-744
78. Simms LA, Doecke JD, Walsh MD, Huang N, Fowler EV, Radford-Smith GL (2008) Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn's disease. Gut 57:903-910
79. Singh SB, Davis AS, Taylor GA, Deretic V (2006) Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313:1438-1441
80. Steinhart AH, Feagan BG, Wong CJ, Vandervoort M, Mikolainis S, Croitoru K, Seidman E, Leddin DJ, Bitton A, Drouin E, Cohen A, Greenberg GR (2002) Combined budesonide and antibiotic therapy for active Crohn's disease: a randomized controlled trial. Gastro 123:33-40
81. Strober W, Fuss IJ, Blumberg RS (2002) The immunology of mucosal models of inflammation. Annu Rev Immunol 20:495-549
82. Stryke D, Kawamoto M, Huang CC, Johns SJ, King LA, Harper CA, Meng EC, Lee RE, Yee A, L'Italien L, Chuang PT, Young SG, Skarnes WC, Babbitt PC, Ferrin TE (2003) BayGenomics: a resource of insertional mutations in mouse embryonic stem cells. Nucleic Acids Res 31:278-281
83. Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, Summers R, Mekhjian H, Greenberger N, Kelly M (1991) Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut 32:1071-1075
84. Targan SR, Hanauer SB, Van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ (1997) A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's disease cA2 study group. N Engl J Med 337:1029-1035
85. Taylor GA, Feng CG, Sher A (2004) p47 GTPases: regulators of immunity to intracellular pathogens. Nat Rev Immunol 4:100-109
86. The Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661-678
87. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI (2007) The human microbiome project. Nature 449:804-810
88. Virgin H (2008) A 'fly-by' killing with a primordial cellular weapon. Nat Immunol 9:827-829
89. Voss E, Wehkamp J, Wehkamp K, Stange EF, Schroder JM, Harder J (2006) NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 281:2005-2011
90. Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss IJ, Kitani A, Strober W (2008) Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J Clin Invest 118:545-559
91. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M, Herrlinger KR, Stallmach A, Noack F, Fritz P, Schroder JM, Bevins CL, Fellermann K, Stange EF (2004) NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 53:1658-1664
92. Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R, Feathers RW, Chu H, Lima H Jr, Fellermann K, Ganz T, Stange EF, Bevins CL (2005) Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci \USA 102:18129-18134
93. Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427-434
94. Xavier RJ, Huett A, Rioux JD (2008) Autophagy as an important process in gut homeostasis and Crohn's disease pathogenesis. Gut 57:717-720
95. Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT (2007) Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27:135-144
96. Yamamoto K, Kiyohara T, Murayama Y, Kihara S, Okamoto Y, Funahashi T, Ito T, Nezu R, Tsutsui S, Miyagawa JI, Tamura S, Matsuzawa Y, Shimomura I, Shinomura Y (2005) Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn's disease. Gut 54:789-796
97. Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T, Simon HU (2006) Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8:1124-1132 .
98. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, SemenzaGL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response tohypoxia. J Biol Chem 283:10892-10903
99. Zhao Z, Thackray LB, Miller BC, Lynn TM, Becker MM, Ward E, Mizushima NN, Denison MR,Virgin HW (2007) Coronavirus replication does not require the autophagy gene ATG5. Autophagy 3:581-585
100. Zhao Z, Fux B, Goodwin M, Dunay IR, Strong D, Miller BC, Cadwell K, Delgado MA, PonpuakM, Green KG, Schmidt RE, Mizushima N, Deretic V, Sibley LD, Virgin HW (2008)Autophagosome-independent essential function for the autophagy protein Atg5 in cellularimmunity to intracellular pathogens. Cell Host Microbe 4:458-469