Apoptotic Cell Clearance in Gut Tissue: Role of Intestinal Regeneration

  • Yasunao Numata
  • Daisuke Hirayama
  • Kohei Wagatsuma
  • Tomoya Iida
  • Hiroshi Nakase
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Intestinal epithelial cells play a critical role in nutrient absorption as well as in protection against infection by pathogenic microorganisms. The cells drop out in a few days, and regeneration occurs subsequently; cells are eliminated by apoptosis. Clearance of dead cells frequently occurs in the intestinal tract, and apoptotic cells and phagocytes cooperate to facilitate cell clearance quickly and efficiently. The complex signaling network for cell clearance is well-understood. In recent years, the mechanism of programmed cell death accompanied by autophagy has been elucidated, and it has become clear that autophagy is involved in inflammation and intestinal tract diseases. In this review, we discuss intestinal regeneration and intestinal diseases through phagocytic clearance and autophagy of apoptotic cells.


Intestinal epithelial cell Apoptosis Phagocytosis Find-me signal Eat-me signal Autophagy Autophagy gene 



Autophagy-related 16-like 1


Adenosine triphosphate


Complement 1q


Crohn’s disease


Cluster of differentiation 14


Cluster of differentiation 31


Cluster of differentiation 36


Cluster of differentiation 47


Cluster of differentiation 91


Chemokine, CX3C motif, ligand 1


Epidermal growth factor




Genome-wide association studies


Including intercellular adhesion molecule 3


Intraepithelial lymphocyte


Low density lipoprotein




Low density lipoprotein receptor-related protein 1


Milk fat globule-EGF-factor 8


Nucleotide-binding oligomerization domain 2




Arginine-Glycine-Aspartic Acid


Reactive oxygen species




Transforming growth factor


Tamm–Horsfall glycoprotein-1


T-cell immunoglobulin and mucin containing protein-1


T-cell immunoglobulin and mucin containing protein-4


Uridine triphosphate


  1. 1.
    Poon IK, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014;14(3):166–80.CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Ogawa N, Shimoyama K, Kawanami T. Apotosisu Saibou no Kuriaransu to Jikomenneki (Clearance of apoptotic cells and autoimmunity). Nihon Rinsho. 2005;63(5):229–32.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Elliott MR, Ravichandran KS. Clearance of apoptotic cells: implications in health and disease. J Cell Biol. 2010;189(7):1059–70.CrossRefPubMedCentralGoogle Scholar
  4. 4.
    Green DR, Oguin TH, Martinez J. The clearance of dying cells: table for two. Cell Death Differ. 2016;23(6):915–26.CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Nagata S, Hanayama R, Kawane K. Autoimmunity and the clearance of dead cells. Cell. 2010;140(5):619–30.CrossRefPubMedCentralGoogle Scholar
  6. 6.
    Saas P, Kaminski S, Perruche S. Prospects of apoptotic cell-based therapies for transplantation and inflammatory diseases. Immunotherapy. 2013;5(10):1055–73.CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Ke P, Shao BZ, Xu ZQ, Chen XW, Liu C. Intestinal autophagy and its pharmacological control in inflammatory bowel disease. Front Immunol. 2016;7:695.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Chekeni FB, Ravichandran KS. The role of nucleotides in apoptotic cell clearance: implications for disease pathogenesis. J Mol Med (Berl). 2011;89(1):13–22.CrossRefGoogle Scholar
  9. 9.
    Lauber K, Blumenthal SG, Waibel M, Wesselborg S. Clearance of apoptotic cells: getting rid of the corpses. Mol Cell. 2014;14(3):277–87.CrossRefGoogle Scholar
  10. 10.
    Ravichandran KS, Lorenz U. Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol. 2007;7(12):964–74.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Elliott MR, Ravichandran KS. The dynamics of apoptotic cell clearance. Dev Cell. 2016;38(2):147–60.CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, Park D, Woodson RI, Ostankovich M, Sharma P, Lysiak JJ, Harden TK, Leitinger N, Ravichandran KS. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature. 2009;461(7261):282–6.CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Gude DR, Alvarez SE, Paugh SW, Mitra P, Yu J, Griffiths R, Barbour SE, Milstien S, Springel S. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J. 2008;22(8):2629–38.CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Lauber K, Bohn E, Kröber SM, Xiao YJ, Blumenthal SG, Lindemann RK, Marini P, Wiedig C, Zobywalski A, Baksh S, Xu Y, Autenrieth IB, Schulze-Osthoff K, Belka C, Stuhler G, Wesselborg S. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell. 2003;113(6):717–30.CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Luo B, Gan W, Liu Z, Shen Z, Wang J, Shi R, Liu Y, Liu Y, Jiang M, Zhang Z, Wu Y. Erythropoeitin signaling in macrophages promotes dying cell clearance and immune tolerance. Immunity. 2016;44(2):287–302.CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Truman LA, Ford CA, Pasikowska M, Pound JD, Wilkinson SJ, Dumitriu IE, Melville L, Melrose LA, Ogden CA, Nibbs R, Graham G, Combadiere C, Gregory CD. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood. 2008;112(13):5026–36.CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Torr EE, Gardner DH, Thomas L, Goodall DM, Bielemeier A, Willetts R, Griffiths HR, Marshall LJ, Devitt A. Apoptotic cell-derived ICAM-3 promotes both macrophage chemoattraction to and tethering of apoptotic cells. Cell Death Differ. 2012;19(4):671–9.CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Weigert A, Cremer S, Schmidt MV, von Knethen A, Angioni C, Geisslinger G, Brüne B. Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells. Blood. 2010;115(17):3531–40.CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Weigert A, Johann AM, von Knethen A, Schmidt H, Geisslinger G, Brüne B. Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate. Blood. 2006;108(5):1635–42.CrossRefPubMedCentralGoogle Scholar
  20. 20.
    Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 1992;148(7):2207–16.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, Bratton DL, Oldenborg PA, Michalak M, Henson PM. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell. 2005;123(2):321–34.CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Segawa K, Suzuki J, Nagata S. Constitutive exposure of phosphatidylserine on viable cells. Proc Natl Acad Sci U S A. 2011;108(48):19246–51.CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002;417(6885):182–7.CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, Nagata S. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science. 2004;304(5674):1147–50.CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110(6):673–87.CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Overstreet MG, Gaylo A, Angermann BR, Hughson A, Hyun YM, Lambert K, Acharya M, Billroth-Maclurg AC, Rosenberg AF, Topham DJ, Yagita H, Kim M, Lacy-Hulbert A, Meier-Schellersheim M, Fowell DJ. Inflammation-induced interstitial migration of effector CD4+ T cells is dependent on integrin αV. Nat Immunol. 2013;14(9):949–58.CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Savill J, Dransfield I, Hogg N, Haslett C. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature. 1990;343(6254):170–3.CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Park D, Tosello Trampont A-C, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW, Ravichandran KS. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature. 2007;450(7168):430–4.CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Kobayashi N, Karisola P, Peña Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity. 2007;27(6):927–40.CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S. Identification of Tim4 as a phosphatidylserine receptor. Nature. 2007;450(7168):435–9.CrossRefPubMedCentralGoogle Scholar
  31. 31.
    Santiago C, Ballesteros A, Martínez Muñoz L, Mellado M, Kaplan GG, Freeman GJ, Casasnovas JM. Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds. Immunity. 2007;27(6):941–51.CrossRefPubMedCentralGoogle Scholar
  32. 32.
    Ezekowitz RA, Sastry K, Bailly P, Warner A. Molecular characterization of the human macrophage mannose receptor: demonstration of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-1 cells. J Exp Med. 1990;172(6):1785–94.CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Ogden CA, Decathelineau A, Hoffmann PR, Bratton D, Ghebrehiwet B, Fadok VA, Henson PM. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med. 2001;194(6):781–95.CrossRefPubMedCentralGoogle Scholar
  34. 34.
    Gregory CD, Devitt A, Moffatt O. Roles of ICAM-3 and CD14 in the recognition and phagocytosis of apoptotic cells by macrophages. Biochem Soc Trans. 1998;26(4):644–9.CrossRefPubMedCentralGoogle Scholar
  35. 35.
    Gordon S. Macrophage-restricted molecules: role in differentiation and activation. Immunol Lett. 1999;65(1-2):5–8.CrossRefPubMedCentralGoogle Scholar
  36. 36.
    Nakaya M, Tanaka M, Okabe Y, Hanayama R, Nagata S. Opposite effects of rho family GTPases on engulfment of apoptotic cells by macrophages. J Biol Chem. 2006;281(13):8836–42.CrossRefPubMedCentralGoogle Scholar
  37. 37.
    Erwig LP, Henson PM. Clearance of apoptotic cells by phagocytes. Cell Death Differ. 2008;15(2):243–50.CrossRefPubMedCentralGoogle Scholar
  38. 38.
    Kitano M, Nakaya M, Nakamura T, Nagata S, Matsuda M. Imaging of Rab5 activity identifies essential regulators for phagosome maturation. Nature. 2008;453(7192):241–5.CrossRefGoogle Scholar
  39. 39.
    Hochreiter Hufford A, Ravichandran KS. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb Perspect Biol. 2013;5(1):a008748.CrossRefPubMedCentralGoogle Scholar
  40. 40.
    Gumienny TL, Brugnera E, Tosello Trampont AC, Kinchen JM, Haney LB, Nishiwaki K, Walk SF, Nemergut ME, Macara IG, Francis R, Schedl T, Qin Y, Van Aelst L, Hengartner MO, Ravichandran KS. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell. 2001;107(1):27–41.CrossRefGoogle Scholar
  41. 41.
    Reddien PW, Horvitz HR. CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nat Cell Biol. 2000;2(3):131–6.CrossRefPubMedCentralGoogle Scholar
  42. 42.
    Wu YC, Horvitz HR. C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature. 1998;392(6675):501–4.CrossRefPubMedCentralGoogle Scholar
  43. 43.
    Zhou Z, Caron E, Hartwieg E, Hall A, Horvitz HR. The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway. Dev Cell. 2001;1(4):477–89.CrossRefPubMedCentralGoogle Scholar
  44. 44.
    Wu YC, Tsai MC, Cheng LC, Chou CJ, Weng NY. C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pathway to control cell migration and cell corpse engulfment. Dev Cell. 2001;1(4):491–502.CrossRefPubMedCentralGoogle Scholar
  45. 45.
    Arandjelovic S, Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol. 2015;16(9):907–17.CrossRefPubMedCentralGoogle Scholar
  46. 46.
    Franz S, Gaipl US, Munoz LE, Sheriff A, Beer A, Kalden JR, Herrmann M. Apoptosis and autoimmunity: when apoptotic cells break their silence. Curr Rheumatol Rep. 2006;8(4):245–7.CrossRefPubMedCentralGoogle Scholar
  47. 47.
    Janko C, Franz S, Munoz LE, Siebig S, Winkler S, Schett G, Lauber K, Sheriff A, van der Vlag J, Herrmann M. CRP/anti-CRP antibodies assembly on the surfaces of cell remnants switches their phagocytic clearance toward inflammation. Front Immunol. 2011;2:70.CrossRefPubMedCentralGoogle Scholar
  48. 48.
    Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015;517(7534):311–20.CrossRefPubMedCentralGoogle Scholar
  49. 49.
    Casciola Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med. 1994;179(4):1317–30.CrossRefPubMedCentralGoogle Scholar
  50. 50.
    Satsu H, Ishimoto Y, Nakano T, Mochizuki T, Iwanaga T, Shimizu M. Induction by activated macrophage-like THP-1 cells of apoptotic and necrotic cell death in intestinal epithelial Caco-2 monolayers via tumor necrosis factor-alpha. Exp Cell Res. 2006;312(19):3909–19.CrossRefPubMedCentralGoogle Scholar
  51. 51.
    Iwanaga T. The involvement of macrophages and lymphocytes in the apoptosis of enterocytes. Arch Histol Cytol. 1995;58(2):151–9.CrossRefPubMedCentralGoogle Scholar
  52. 52.
    Merger M, Viney JL, Borojevic R, Steele-Norwood D, Zhou P, Clark DA, Riddell R, Maric R, Podack ER, Croitoru K. Defining the roles of perforin, Fas/FasL, and tumour necrosis factor alpha in T cell induced mucosal damage in the mouse intestine. Gut. 2002;51(2):155–63.CrossRefPubMedCentralGoogle Scholar
  53. 53.
    Iwanaga T. Choujouhisaibou no Saibousi to sono Haijo (Apoptosis of intestinal epithelial cells and their disposal). Igaku no ayumi (J Clin Exp Med). 2008;225(6):507–10.Google Scholar
  54. 54.
    Huang FP, Platt N, Wykes M, Major JR, Powell TJ, Jenkins CD, MacPherson GG. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med. 2000;191(3):435–44.CrossRefPubMedCentralGoogle Scholar
  55. 55.
    Iida T, Onodera K, Nakase H. Role of autophagy in the pathogenesis of inflammatory bowel disease. World J Gastroenterol. 2017;23(11):1944–53.CrossRefPubMedCentralGoogle Scholar
  56. 56.
    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D’Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, International IBD Genetics Consortium (IIBDGC), Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.CrossRefPubMedCentralGoogle Scholar
  57. 57.
    Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011;469(7330):323–35.CrossRefPubMedCentralGoogle Scholar
  58. 58.
    Hooper KM, Barlow PG, Stevens C, Henderson P. Inflammatory bowel disease drugs: a focus on autophagy. J Crohns Colitis. 2017;11(1):118–27.CrossRefPubMedCentralGoogle Scholar
  59. 59.
    Shao B-Z, Han B-Z, Zeng Y-X, Su D-F, Liu C. The roles of macrophage autophagy in atherosclerosis. Acta Pharmacol Sin. 2016;37(2):150–6.CrossRefPubMedCentralGoogle Scholar
  60. 60.
    Liu NA, Shi Y, Zhuang S. Autophagy in chronic kidney diseases. Kidney Dis (Basel). 2016;2(1):37–45.CrossRefGoogle Scholar
  61. 61.
    Gump JM, Thorburn A. Autophagy and apoptosis: what is the connection? Trends Cell Biol. 2011;21(7):387–92.CrossRefPubMedCentralGoogle Scholar
  62. 62.
    Canonico B, Cesarini E, Salucci S, Luchetti F, Falcieri E, Di Sario G, Palma F, Papa S. Defective autophagy, mitochondrial clearance and lipophagy in niemann-pick type B lymphocytes. PLoS One. 2016;11(10):e0165780.CrossRefPubMedCentralGoogle Scholar
  63. 63.
    Deretic V. Autophagy in leukocytes and other cells: mechanisms, subsystem organization, selectivity, and links to innate immunity. J Leukoc Biol. 2016;100(5):969–78.CrossRefPubMedCentralGoogle Scholar
  64. 64.
    Gao S, Sun D, Wang G, Zhang J, Jiang Y, Li G, Zhang K, Wang L, Huang J, Chen L. Growth inhibitory effect of paratocarpin E, a prenylated chalcone isolated from Euphorbia humifusa Wild., by induction of autophagy and apoptosis in human breast cancer cells. Bioorg Chem. 2016;69:121–8.CrossRefPubMedCentralGoogle Scholar
  65. 65.
    Li Y, Yu G, Yuan S, Tan C, Xie J, Ding Y, Lian P, Fu L, Hou Q, Xu B, Wang H. 14,15-Epoxyeicosatrienoic acid suppresses cigarette smoke condensate-induced inflammation in lung epithelial cells by inhibiting autophagy. Am J Physiol Lung Cell Mol Physiol. 2016;311(5):L970–80.CrossRefPubMedCentralGoogle Scholar
  66. 66.
    Wells JM, Rossi O, Meijerink M, Van Baarlen P. Epithelial crosstalk at the microbiota-mucosal interface. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4607–14.CrossRefPubMedCentralGoogle Scholar
  67. 67.
    Goto Y, Kiyono H. Epithelial barrier: an interface for the cross-communication between gut flora and immune system. Immunol Rev. 2012;245(1):147–63.CrossRefPubMedCentralGoogle Scholar
  68. 68.
    Moran AP, Gupta A, Joshi L. Sweet-talk: role of host glycosylation in bacterial pathogenesis of the gastrointestinal tract. Gut. 2011;60(10):1412–25.CrossRefPubMedCentralGoogle Scholar
  69. 69.
    Hansson GC. Role of mucus layers in gut infection and inflammation. Curr Opin Microbiol. 2012;15(1):57–62.CrossRefPubMedCentralGoogle Scholar
  70. 70.
    Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. Am J Anat. 1974;141(4):537–61.CrossRefPubMedCentralGoogle Scholar
  71. 71.
    Okumura R, Kurakawa T, Nakano T, Kayama H, Kinoshita M, Motooka D, Gotoh K, Kimura T, Kamiyama N, Kusu T, Ueda Y, Wu H, Iijima H, Barman S, Osawa H, Matsuno H, Nishimura J, Ohba Y, Nakamura S, Iida T, Yamamoto M, Umemoto E, Sano K, Takeda K. Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia. Nature. 2016;532(7597):117–21.CrossRefPubMedCentralGoogle Scholar
  72. 72.
    Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE, Head RD, Xavier R, Stappenbeck TS, Virgin HW. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell. 2010;141(7):1135–45.CrossRefPubMedCentralGoogle Scholar
  73. 73.
    Okamoto R, Watanabe M. Functional relevance of intestinal epithelial cells in inflammatory bowel disease. Nihon Rinsho Meneki Gakkai Kaishi (Jpn J Clin Immunol). 2016;39(6):522–7.CrossRefGoogle Scholar
  74. 74.
    de Souza HSP, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol. 2016;13(1):13–27.CrossRefPubMedCentralGoogle Scholar
  75. 75.
    Inohara N, Ogura Y, Nuñez G. Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr Opin Microbiol. 2002;5(1):76–80.CrossRefPubMedCentralGoogle Scholar
  76. 76.
    Wehkamp J, Harder J, Weichenthal M, Schwab M, Schäffeler E, Schlee M, Herrlinger KR, Stallmach A, Noack F, Fritz P, Schröder JM, Bevins CL, Fellermann K, Stange EF. NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut. 2004;53(11):1658–64.CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Yasunao Numata
    • 1
  • Daisuke Hirayama
    • 1
  • Kohei Wagatsuma
    • 1
  • Tomoya Iida
    • 1
  • Hiroshi Nakase
    • 1
  1. 1.Department of Gastroenterology and HepatologySapporo Medical University School of MedicineSapporoJapan

Personalised recommendations