Experimental Models of Inflammatory Bowel Diseases

Patricia Kiesler1, Ivan J. Fuss1, Warren Strober1
1Mucosal Immunity Section, Laboratory of Host Defenses, National Institutes of Health, Bethesda, Maryland

Tài liệu tham khảo

Hermiston, 1995, Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin, Science, 270, 1203, 10.1126/science.270.5239.1203 Okayasu, 1990, A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice, Gastroenterology, 98, 694, 10.1016/0016-5085(90)90290-H Cooper, 1993, Clinicopathologic study of dextran sulfate sodium experimental murine colitis, Lab Invest, 69, 238 Dieleman, 1994, Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice, Gastroenterology, 107, 1643, 10.1016/0016-5085(94)90803-6 Krieglstein, 2002, Collagen-binding integrin α1β1 regulates intestinal inflammation in experimental colitis, J Clin Invest, 110, 1773, 10.1172/JCI200215256 Fukata, 2005, Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis, Am J Physiol Gastrointest Liver Physiol, 288, G1055, 10.1152/ajpgi.00328.2004 Pull, 2005, Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury, Proc Natl Acad Sci USA, 102, 99, 10.1073/pnas.0405979102 Dieleman, 1998, Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by TH1 and Th2 cytokines, Clin Exp Immunol, 114, 385, 10.1046/j.1365-2249.1998.00728.x Chami, 2014, The role of CXCR3 in DSS-induced colitis, PLoS One, 9, e101622, 10.1371/journal.pone.0101622 Rakoff-Nahoum, 2004, Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis, Cell, 118, 229, 10.1016/j.cell.2004.07.002 Cario, 2007, Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function, Gastroenterology, 132, 1359, 10.1053/j.gastro.2007.02.056 Iliev, 2012, Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis, Science, 336, 1314, 10.1126/science.1221789 Dupaul-Chicoine, 2010, Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases, Immunity, 32, 367, 10.1016/j.immuni.2010.02.012 Zaki, 2010, The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis, Immunity, 32, 379, 10.1016/j.immuni.2010.03.003 Elinav, 2011, NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis, Cell, 145, 745, 10.1016/j.cell.2011.04.022 Sokol, 2013, Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice, Gastroenterology, 145, 591, 10.1053/j.gastro.2013.05.047 Hsu, 2010, Toll-like receptor 4 differentially regulates epidermal growth factor-related growth factors in response to intestinal mucosal injury, Lab Invest, 90, 1295, 10.1038/labinvest.2010.100 Egea, 2013, GM-CSF produced by nonhematopoietic cells is required for early epithelial cell proliferation and repair of injured colonic mucosa, J Immunol, 190, 1702, 10.4049/jimmunol.1202368 Sedhom, 2013, Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice, Gut, 62, 1714, 10.1136/gutjnl-2011-301785 Koch, 2011, The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair, Gastroenterology, 141, 259, 10.1053/j.gastro.2011.03.043 Siegmund, 2001, IL-1 beta-converting enzyme (caspase-1) in intestinal inflammation, Proc Natl Acad Sci USA, 98, 13249, 10.1073/pnas.231473998 Maeda, 2005, Nod2 mutation in Crohn’s disease potentiates NF-κB activity and IL-1β processing, Science, 307, 734, 10.1126/science.1103685 Saitoh, 2008, Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production, Nature, 456, 264, 10.1038/nature07383 Bersudsky, 2014, Non-redundant properties of IL-1α and IL-1β during acute colon inflammation in mice, Gut, 63, 598, 10.1136/gutjnl-2012-303329 Siegmund, 2001, Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production, Am J Physiol Regul Integr Comp Physiol, 281, R1264, 10.1152/ajpregu.2001.281.4.R1264 Sivakumar, 2002, Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage, Gut, 50, 812, 10.1136/gut.50.6.812 Takagi, 2003, Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice, Scand J Gastroenterol, 38, 837, 10.1080/00365520310004047 Reuter, 2004, Commentary: the role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe?, Eur J Immunol, 34, 2347, 10.1002/eji.200425351 Salcedo, 2010, MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18, J Exp Med, 207, 1625, 10.1084/jem.20100199 Huber, 2012, IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine, Nature, 491, 259, 10.1038/nature11535 Rutter, 2004, Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis, Gastroenterology, 126, 451, 10.1053/j.gastro.2003.11.010 Jess, 2006, Risk of intestinal cancer in inflammatory bowel disease: a population-based study from olmsted county, Minnesota, Gastroenterology, 130, 1039, 10.1053/j.gastro.2005.12.037 Gupta, 2007, Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study, Gastroenterology, 133, 1099, 10.1053/j.gastro.2007.08.001 Tanaka, 2003, A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate, Cancer Sci, 94, 965, 10.1111/j.1349-7006.2003.tb01386.x Wang, 2014, Neutrophil infiltration favors colitis-associated tumorigenesis by activating the interleukin-1 (IL-1)/IL-6 axis, Mucosal Immunol, 7, 1106, 10.1038/mi.2013.126 Natividad, 2012, Commensal and probiotic bacteria influence intestinal barrier function and susceptibility to colitis in Nod1−/−; Nod2−/− mice, Inflamm Bowel Dis, 18, 1434, 10.1002/ibd.22848 Chen, 2011, A functional role for Nlrp6 in intestinal inflammation and tumorigenesis, J Immunol, 186, 7187, 10.4049/jimmunol.1100412 Normand, 2011, Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury, Proc Natl Acad Sci USA, 108, 9601, 10.1073/pnas.1100981108 Hu, 2013, Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer, Proc Natl Acad Sci USA, 110, 9862, 10.1073/pnas.1307575110 Neurath, 2000, TNBS-colitis, Int Rev Immunol, 19, 51, 10.3109/08830180009048389 Neurath, 1995, Antibodies to interleukin 12 abrogate established experimental colitis in mice, J Exp Med, 182, 1281, 10.1084/jem.182.5.1281 Strober, 2011, Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases, Gastroenterology, 140, 1756, 10.1053/j.gastro.2011.02.016 Davidson, 1998, IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice, J Immunol, 161, 3143, 10.4049/jimmunol.161.6.3143 Simpson, 1998, T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/Signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells, J Exp Med, 187, 1225, 10.1084/jem.187.8.1225 Mannon, 2004, Anti-interleukin-12 antibody for active Crohn’s disease, N Engl J Med, 351, 2069, 10.1056/NEJMoa033402 Sandborn, 2008, Ustekinumab Crohn’s Disease Study G. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease, Gastroenterology, 135, 1130, 10.1053/j.gastro.2008.07.014 Oppmann, 2000, Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12, Immunity, 13, 715, 10.1016/S1074-7613(00)00070-4 Becker, 2006, Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis, J Immunol, 177, 2760, 10.4049/jimmunol.177.5.2760 Hue, 2006, Interleukin-23 drives innate and T cell-mediated intestinal inflammation, J Exp Med, 203, 2473, 10.1084/jem.20061099 O’Connor, 2009, A protective function for interleukin 17A in T cell-mediated intestinal inflammation, Nat Immunol, 10, 603, 10.1038/ni.1736 Meylan, 2011, The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation, Mucosal Immunol, 4, 172, 10.1038/mi.2010.67 Dohi, 1999, Hapten-induced colitis is associated with colonic patch hypertrophy and T helper cell 2-type responses, J Exp Med, 189, 1169, 10.1084/jem.189.8.1169 Dohi, 2000, Mice deficient in Th1- and Th2-type cytokines develop distinct forms of hapten-induced colitis, Gastroenterology, 119, 724, 10.1053/gast.2000.16500 Fichtner-Feigl, 2005, Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-kappa B decoy oligonucleotides, J Clin Invest, 115, 3057, 10.1172/JCI24792 Lawrance, 2003, A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B, Gastroenterology, 125, 1750, 10.1053/j.gastro.2003.08.027 Fichtner-Feigl, 2008, IL-13 signaling via IL-13R alpha2 induces major downstream fibrogenic factors mediating fibrosis in chronic TNBS colitis, Gastroenterology, 135, 2003, 10.1053/j.gastro.2008.08.055 Koon, 2010, Substance P modulates colitis-associated fibrosis, Am J Pathol, 177, 2300, 10.2353/ajpath.2010.100314 Yoo, 2015, Antifibrogenic effects of the antimicrobial peptide cathelicidin in murine colitis-associated fibrosis, Cell Mol Gastroenterol Hepatol, 1, 55, 10.1016/j.jcmgh.2014.08.001 Shih, 2014, Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis, Mucosal Immunol, 7, 1492, 10.1038/mi.2014.37 Fichtner-Feigl, 2014, IL-13 orchestrates resolution of chronic intestinal inflammation via phosphorylation of glycogen synthase kinase-3β, J Immunol, 192, 3969, 10.4049/jimmunol.1301072 Fiorucci, 2002, Importance of innate immunity and collagen binding integrin alpha1beta1 in TNBS-induced colitis, Immunity, 17, 769, 10.1016/S1074-7613(02)00476-4 Watanabe, 2014, NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6, Mucosal Immunol, 7, 1312, 10.1038/mi.2014.19 Boirivant, 2008, A transient breach in the epithelial barrier leads to regulatory T-cell generation and resistance to experimental colitis, Gastroenterology, 135, 1612, 10.1053/j.gastro.2008.07.028 Girardin, 2003, Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection, J Biol Chem, 278, 8869, 10.1074/jbc.C200651200 Amendola, 2014, Nod2 deficiency is associated with an increased mucosal immunoregulatory response to commensal microorganisms, Mucosal Immunol, 7, 391, 10.1038/mi.2013.58 Neurath, 1996, Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance, J Exp Med, 183, 2605, 10.1084/jem.183.6.2605 Fuss, 2002, The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis, J Immunol, 168, 900, 10.4049/jimmunol.168.2.900 Boirivant, 2005, Regulatory cells induced by feeding TNP-haptenated colonic protein cross-protect mice from colitis induced by an unrelated hapten, Inflamm Bowel Dis, 11, 48, 10.1097/00054725-200501000-00007 Boirivant, 1998, Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4, J Exp Med, 188, 1929, 10.1084/jem.188.10.1929 Heller, 2002, Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells, Immunity, 17, 629, 10.1016/S1074-7613(02)00453-3 Olszak, 2012, Microbial exposure during early life has persistent effects on natural killer T cell function, Science, 336, 489, 10.1126/science.1219328 Fuss, 2004, Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis, J Clin Invest, 113, 1490, 10.1172/JCI19836 Heller, 2005, Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution, Gastroenterology, 129, 550, 10.1016/j.gastro.2005.05.002 Dohi, 2009, TWEAK/Fn14 pathway: a nonredundant role in intestinal damage in mice through a TWEAK/intestinal epithelial cell axis, Gastroenterology, 136, 912, 10.1053/j.gastro.2008.11.017 Kawashima, 2011, Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis, Gastroenterology, 141, 2119, 10.1053/j.gastro.2011.08.040 Krug, 2014, Impaired epithelial barrier for macromolecules in ulcerative colitis is caused by downregulation of the tricellular tight junction protein tricellulin, mediated by the interleukin-13 receptor α2-activated pathway. [Abstract 410.], Gasteroenterology, 146, S88, 10.1016/S0016-5085(14)60318-8 Weber, 2010, Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity, J Biol Chem, 285, 12037, 10.1074/jbc.M109.064808 Gerlach, 2014, TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells, Nat Immunol, 15, 676, 10.1038/ni.2920 Camelo, 2012, Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13, J Gastroenterol, 47, 1198, 10.1007/s00535-012-0591-2 Fuss, 2014, IL-13Rα2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis, Gut, 63, 1728, 10.1136/gutjnl-2013-305671 Powrie, 1993, Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice, Int Immunol, 5, 1461, 10.1093/intimm/5.11.1461 Powrie, 1994, Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells, Immunity, 1, 553, 10.1016/1074-7613(94)90045-0 Read, 2000, Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation, J Exp Med, 192, 295, 10.1084/jem.192.2.295 Leach, 1996, Inflammatory bowel disease in C.B-17 scid mice reconstituted with the CD45RBhigh subset of CD4+ T cells, Am J Pathol, 148, 1503 Vignali, 2008, How regulatory T cells work, Nat Rev Immunol, 8, 523, 10.1038/nri2343 Shevach, 2009, Mechanisms of foxp3+ T regulatory cell-mediated suppression, Immunity, 30, 636, 10.1016/j.immuni.2009.04.010 Asseman, 1999, An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation, J Exp Med, 190, 995, 10.1084/jem.190.7.995 Davidson, 1996, T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice, J Exp Med, 184, 241, 10.1084/jem.184.1.241 Murai, 2009, Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis, Nat Immunol, 10, 1178, 10.1038/ni.1791 Powrie, 1996, A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlow CD4+ T cells, J Exp Med, 183, 2669, 10.1084/jem.183.6.2669 Nakamura, 2001, Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor beta, J Exp Med, 194, 629, 10.1084/jem.194.5.629 Nakamura, 2004, TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice, J Immunol, 172, 834, 10.4049/jimmunol.172.2.834 Fahlen, 2005, T cells that cannot respond to TGF-beta escape control by CD4+CD25+ regulatory T cells, J Exp Med, 201, 737, 10.1084/jem.20040685 Neurath, 2002, The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease, J Exp Med, 195, 1129, 10.1084/jem.20011956 Ahern, 2010, Interleukin-23 drives intestinal inflammation through direct activity on T cells, Immunity, 33, 279, 10.1016/j.immuni.2010.08.010 Elson, 2007, Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice, Gastroenterology, 132, 2359, 10.1053/j.gastro.2007.03.104 Leppkes, 2009, RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F, Gastroenterology, 136, 257, 10.1053/j.gastro.2008.10.018 Mikami, 2010, Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis, Eur J Immunol, 40, 2409, 10.1002/eji.201040379 Griseri, 2010, OX40 is required for regulatory T cell-mediated control of colitis, J Exp Med, 207, 699, 10.1084/jem.20091618 Sakuraba, 2009, Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn’s disease, Gastroenterology, 137, 1736, 10.1053/j.gastro.2009.07.049 Sujino, 2011, Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells, Gastroenterology, 141, 1014, 10.1053/j.gastro.2011.05.052 Lee, 2009, Late developmental plasticity in the T helper 17 lineage, Immunity, 30, 92, 10.1016/j.immuni.2008.11.005 Izcue, 2008, Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis, Immunity, 28, 559, 10.1016/j.immuni.2008.02.019 Schiering, 2014, The alarmin IL-33 promotes regulatory T-cell function in the intestine, Nature, 513, 564, 10.1038/nature13577 Wang, 2011, An essential role of the transcription factor GATA-3 for the function of regulatory T cells, Immunity, 35, 337, 10.1016/j.immuni.2011.08.012 Wohlfert, 2011, GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice, J Clin Invest, 121, 4503, 10.1172/JCI57456 Beltran, 2010, Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease, Inflamm Bowel Dis, 16, 1097, 10.1002/ibd.21175 Kobori, 2010, Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis, J Gastroenterol, 45, 999, 10.1007/s00535-010-0245-1 Palmer, 2011, Interleukin-33 biology with potential insights into human diseases, Nat Rev Rheumatol, 7, 321, 10.1038/nrrheum.2011.53 Pastorelli, 2010, Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis, Proc Natl Acad Sci U S A, 107, 8017, 10.1073/pnas.0912678107 Seidelin, 2010, IL-33 is upregulated in colonocytes of ulcerative colitis, Immunol Lett, 128, 80, 10.1016/j.imlet.2009.11.001 Veldhoen, 2006, TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells, Immunity, 24, 179, 10.1016/j.immuni.2006.01.001 Zhou, 2007, IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways, Nat Immunol, 8, 967, 10.1038/ni1488 Ghoreschi, 2010, Generation of pathogenic TH17 cells in the absence of TGF-beta signalling, Nature, 467, 967, 10.1038/nature09447 McGeachy, 2007, TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology, Nat Immunol, 8, 1390, 10.1038/ni1539 Lee, 2012, Induction and molecular signature of pathogenic TH17 cells, Nat Immunol, 13, 991, 10.1038/ni.2416 Griseri, 2012, Dysregulated hematopoietic stem and progenitor cell activity promotes interleukin-23-driven chronic intestinal inflammation, Immunity, 37, 1116, 10.1016/j.immuni.2012.08.025 Buonocore, 2010, Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology, Nature, 464, 1371, 10.1038/nature08949 Geremia, 2011, IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease, J Exp Med, 208, 1127, 10.1084/jem.20101712 Dianda, 1997, T cell receptor-alpha beta-deficient mice fail to develop colitis in the absence of a microbial environment, Am J Pathol, 150, 91 Sellon, 1998, Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice, Infect Immun, 66, 5224, 10.1128/IAI.66.11.5224-5231.1998 Garrett, 2007, Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system, Cell, 131, 33, 10.1016/j.cell.2007.08.017 Schultz, 1999, IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation, Am J Physiol, 276, G1461 Aranda, 1997, Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4+, CD45RBhigh T cells to SCID recipients, J Immunol, 158, 3464, 10.4049/jimmunol.158.7.3464 Palm, 2014, Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease, Cell, 158, 1000, 10.1016/j.cell.2014.08.006 Mazmanian, 2008, A microbial symbiosis factor prevents intestinal inflammatory disease, Nature, 453, 620, 10.1038/nature07008 Round, 2010, Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota, Proc Natl Acad Sci USA, 107, 12204, 10.1073/pnas.0909122107 Atarashi, 2011, Induction of colonic regulatory T cells by indigenous Clostridium species, Science, 331, 337, 10.1126/science.1198469 Arpaia, 2013, Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation, Nature, 504, 451, 10.1038/nature12726 Lord, 2012, Paradoxically increased FOXP3+ T cells in IBD do not preferentially express the isoform of FOXP3 lacking exon 2, Dig Dis Sci, 57, 2846, 10.1007/s10620-012-2292-3 Kuhn, 1993, Interleukin-10-deficient mice develop chronic enterocolitis, Cell, 75, 263, 10.1016/0092-8674(93)80068-P Franke, 2008, Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility, Nat Genet, 40, 1319, 10.1038/ng.221 Franke, 2010, Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci, Nat Genet, 42, 1118, 10.1038/ng.717 Glocker, 2009, Inflammatory bowel disease and mutations affecting the interleukin-10 receptor, N Engl J Med, 361, 2033, 10.1056/NEJMoa0907206 Berg, 1996, Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4+ TH1-like responses, J Clin Invest, 98, 1010, 10.1172/JCI118861 Spencer, 2002, Distinct inflammatory mechanisms mediate early versus late colitis in mice, Gastroenterology, 122, 94, 10.1053/gast.2002.30308 Spencer, 1998, The orphan receptor CRF2–4 is an essential subunit of the interleukin 10 receptor, J Exp Med, 187, 571, 10.1084/jem.187.4.571 Martins, 2006, Transcriptional repressor Blimp-1 regulates T cell homeostasis and function, Nat Immunol, 7, 457, 10.1038/ni1320 Roers, 2004, T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation, J Exp Med, 200, 1289, 10.1084/jem.20041789 Rubtsov, 2008, Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces, Immunity, 28, 546, 10.1016/j.immuni.2008.02.017 Rakoff-Nahoum, 2006, Role of toll-like receptors in spontaneous commensal-dependent colitis, Immunity, 25, 319, 10.1016/j.immuni.2006.06.010 Hoshi, 2012, MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice, Nat Commun, 3, 1120, 10.1038/ncomms2113 Narushima, 2003, Evidence for oxidative stress in NSAID-induced colitis in IL10−/− mice, Free Radic Biol Med, 34, 1153, 10.1016/S0891-5849(03)00065-0 Im, 2014, Disruption of Pten speeds onset and increases severity of spontaneous colitis in Il10−/− mice, Gastroenterology, 147, 667, 10.1053/j.gastro.2014.05.034 Zigmond, 2014, Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis, Immunity, 40, 720, 10.1016/j.immuni.2014.03.012 Shouval, 2014, Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function, Immunity, 40, 706, 10.1016/j.immuni.2014.03.011 Velcich, 2002, Colorectal cancer in mice genetically deficient in the mucin Muc2, Science, 295, 1726, 10.1126/science.1069094 Van der Sluis, 2006, Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection, Gastroenterology, 131, 117, 10.1053/j.gastro.2006.04.020 An, 2007, Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans, J Exp Med, 204, 1417, 10.1084/jem.20061929 Fu, 2011, Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice, J Clin Invest, 121, 1657, 10.1172/JCI45538 Panwala, 1998, A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis, J Immunol, 161, 5733, 10.4049/jimmunol.161.10.5733 Resta-Lenert, 2005, Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a−/− mice, Am J Physiol Gastrointest Liver Physiol, 289, G153, 10.1152/ajpgi.00395.2004 Collett, 2005, Comparison of P-glycoprotein-mediated drug-digoxin interactions in Caco-2 with human and rodent intestine: relevance to in vivo prediction, Eur J Pharm Sci, 26, 386, 10.1016/j.ejps.2005.07.013 Powell, 2012, The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells, Immunity, 37, 674, 10.1016/j.immuni.2012.09.008 Nenci, 2007, Epithelial NEMO links innate immunity to chronic intestinal inflammation, Nature, 446, 557, 10.1038/nature05698 Zaph, 2007, Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis, Nature, 446, 552, 10.1038/nature05590 Matsumoto, 1998, Inflammatory bowel disease-like enteritis and caecitis in a senescence accelerated mouse P1/Yit strain, Gut, 43, 71, 10.1136/gut.43.1.71 Kaser, 2008, XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease, Cell, 134, 743, 10.1016/j.cell.2008.07.021 Adolph, 2013, Paneth cells as a site of origin for intestinal inflammation, Nature, 503, 272, 10.1038/nature12599 Takeda, 1999, Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils, Immunity, 10, 39, 10.1016/S1074-7613(00)80005-9 Kobayashi, 2003, Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice, J Clin Invest, 111, 1297, 10.1172/JCI17085 Pickert, 2009, STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing, J Exp Med, 206, 1465, 10.1084/jem.20082683 Watanabe, 1998, Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa, J Exp Med, 187, 389, 10.1084/jem.187.3.389 Totsuka, 2007, IL-7 Is essential for the development and the persistence of chronic colitis, J Immunol, 178, 4737, 10.4049/jimmunol.178.8.4737 Nemoto, 2007, Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis, Gastroenterology, 132, 176, 10.1053/j.gastro.2006.10.035 Nemoto, 2009, Long-lived colitogenic CD4+ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis, J Immunol, 183, 5059, 10.4049/jimmunol.0803684 Nemoto, 2011, Luminal CD4+ T cells penetrate gut epithelial monolayers and egress from lamina propria to blood circulation, Gastroenterology, 141, 2130, 10.1053/j.gastro.2011.08.035 Nemoto, 2013, Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells, Gut, 62, 1142, 10.1136/gutjnl-2012-302029