Advertisement

Virchows Archiv

, Volume 473, Issue 1, pp 71–83 | Cite as

Notch inhibition counteracts Paneth cell death in absence of caspase-8

  • M. K. Jeon
  • E. Kaemmerer
  • U. Schneider
  • M. Schiffer
  • C. Klaus
  • J. Hennings
  • T. Clahsen
  • T. Ackerstaff
  • M. Niggemann
  • A. Schippers
  • T. Longerich
  • G. Sellge
  • C. Trautwein
  • N. Wagner
  • C. Liedtke
  • N. Gassler
Original Article

Abstract

Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity. Here, we found that pharmacological Notch inhibition with dibenzazepine (DBZ) is able to essentially rescue the loss of Paneth cells, deescalate the inflammatory phenotype, and reduce intestinal permeability in casp8∆int mice. The secretory cell metaplasia in DBZ-treated casp8∆int animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8∆int background. Our data suggest that casp8 acts in the intestinal Notch network.

Keywords

Caspase 8 Crohn’s disease Notch Paneth cell 

Abbreviations

casp8

Caspase-8

casp8∆int mice

Intestinal casp8 knockout mice

DBZ

Dipenzazepine

Shp2

Src homolog region 2-containing protein tyrosine phosphatase 2

MAPK

Mitogen-activated protein kinase

Rip3

Receptor-interacting protein 3

FITC-dextran

Fluorescein isothiocyanate-dextran

LMP

Laser microdissected probe

AB-PAS

Alcian blue-periodic acid-Schiff reagent

Notes

Acknowledgements

The authors thank P. Akens for typing and proofreading the manuscript.

Funding

The work was partially supported by Deutsche Forschungsgemeinschaft (DFG GA 785/5–1) and Deutsche Krebshilfe (GA 109313).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Ostaff MJ, Stange EF, Wehkamp J (2013) Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med 5:1465–1483CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Hodin CM, Lenaerts K, Grootjans J, de Haan JJ, Hadfoune M, Verheyen FK, Kiyama H, Heineman E, Buurman WA (2011) Starvation compromises Paneth cells. Am J Pathol 179:2885–2893CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Barker N, van de Wetering M, Clevers H (2008) The intestinal stem cell. Genes Dev 22:1856–1864CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M, Barker N, Shroyer NF, van de Wetering M, Clevers H (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469:415–418CrossRefPubMedGoogle Scholar
  5. 5.
    Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Böck J, Martinez-Naves E, Glickman JN, Tschurtschenthaler M, Hartwig J, Hosomi S, Flak MB, Cusick JL, Kohno K, Iwawaki T, Billmann-Born S, Raine T, Bharti R, Lucius R, Kweon MN, Marciniak SJ, Choi A, Hagen SJ, Schreiber S, Rosenstiel P, Kaser A, Blumberg RS (2013) Paneth cells as a site of origin for intestinal inflammation. Nature 503:272–276CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bolós V, Grego-Bessa J, de la Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28:339–363CrossRefPubMedGoogle Scholar
  7. 7.
    Fiúza UM, Arias AM (2007) Cell and molecular biology of notch. J Endocrinol 194:459–474CrossRefPubMedGoogle Scholar
  8. 8.
    Li Y, Ma J, Qian X, Wu Q, Xia J, Miele L, Sarkar FH, Wang Z (2013) Regulation of EMT by notch signaling pathway in tumor progression. Curr Cancer Drug Targets 13:957–962CrossRefPubMedGoogle Scholar
  9. 9.
    Rodilla V, Villanueva A, Obrador-Hevia A, Robert-Moreno A, Fernández-Majada V, Grilli A, López-Bigas N, Bellora N, Albà MM, Torres F, Duñach M, Sanjuan X, Gonzalez S, Gridley T, Capella G, Bigas A, Espinosa L (2009) Jagged1 is the pathological link between Wnt and notch pathways in colorectal cancer. Proc Natl Acad Sci U S A 106:6315–6320CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    D’Souza B, Meloty-Kapella L, Weinmaster G (2010) Canonical and non-canonical notch ligands. Curr Top Dev Biol 92:73–129CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Andersen P, Uosaki H, Shenje LT, Kwon C (2012) Non-canonical notch signaling: emerging role and mechanism. Trends Cell Biol 22:257–265CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Heuberger J, Kosel F, Qi J, Grossmann KS, Rajewsky K, Birchmeier W (2014) Shp2/MAPK signaling controls goblet/Paneth cell fate decisions in the intestine. Proc Natl Acad Sci U S A 111:3472–3477CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Shroyer NF, Wallis D, Venken KJ, Bellen HJ, Zoghbi HY (2005) Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev 19:2412–2417CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kim TH, Shivdasani RA (2011) Genetic evidence that intestinal notch functions vary regionally and operate through a common mechanism of Math1 repression. J Biol Chem 286:11427–11433CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    VanDussen KL, Carulli AJ, Keeley TM, Patel SR, Puthoff BJ, Magness ST, Tran IT, Maillard I, Siebel C, Kolterud Å, Grosse AS, Gumucio DL, Ernst SA, Tsai YH, Dempsey PJ, Samuelson LC (2012) Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 139:488–497CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Tian H, Biehs B, Chiu C, Siebel CW, Wu Y, Costa M, de Sauvage FJ, Klein OD (2015) Opposing activities of notch and Wnt signaling regulate intestinal stem cells and gut homeostasis. Cell Rep 11:33–42CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Günther C, Neumann H, Neurath MF, Becker C (2013) Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut 62:1062–1071CrossRefPubMedGoogle Scholar
  18. 18.
    Günther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C (2011) Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477:335–339CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Liedtke C, Bangen JM, Freimuth J, Beraza N, Lambertz D, Cubero FJ, Hatting M, Karlmark KR, Streetz KL, Krombach GA, Tacke F, Gassler N, Riethmacher D, Trautwein C (2011) Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. Gastroenterology 141:2176–2187CrossRefPubMedGoogle Scholar
  20. 20.
    Pinto D, Robine S, Jaisser F, El Marjou E, Louvard D (1999) Regulatory sequences of the mouse villin gene that efficiently drive transgenic expression in immature and differentiated epithelial cells of small and large intestines. J Biol Chem 274:6476–6482CrossRefPubMedGoogle Scholar
  21. 21.
    Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159CrossRefPubMedGoogle Scholar
  22. 22.
    van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959–963CrossRefPubMedGoogle Scholar
  23. 23.
    Farin HF, Jordens I, Mosa MH, Basak O, Korving J, Tauriello DV, de Punder K, Angers S, Peters PJ, Maurice MM, Clevers H (2016) Visualization of a short-range Wnt gradient in the intestinal stem-cell niche. Nature 530:340–343CrossRefPubMedGoogle Scholar
  24. 24.
    Demitrack ES, Samuelson LC (2016) Notch regulation of gastrointestinal stem cells. J Physiol 594:4791–4803CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Horvay K, Abud HE (2013) Regulation of intestinal stem cells by Wnt and notch signalling. Adv Exp Med Biol 786:175–186CrossRefPubMedGoogle Scholar
  26. 26.
    Andreu P, Colnot S, Godard C, Gad S, Chafey P, Niwa-Kawakita M, Laurent-Puig P, Kahn A, Robine S, Perret C, Romagnolo B (2005) Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development 132:1443–1451CrossRefPubMedGoogle Scholar
  27. 27.
    van Es JH, Jay P, Gregorieff A, van Gijn ME, Jonkheer S, Hatzis P, Thiele A, van den Born M, Begthel H, Brabletz T, Taketo MM, Clevers H (2005) Wnt signaling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol 7:381–386CrossRefPubMedGoogle Scholar
  28. 28.
    Muñoz J, Stange DE, Schepers AG, van de Wetering M, Koo BK, Itzkovitz S, Volckmann R, Kung KS, Koster J, Radulescu S, Myant K, Versteeg R, Sansom OJ, van Es JH, Barker N, van Oudenaarden A, Mohammed S, Heck AJ, Clevers H (2012) The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent “+4” cell markers. EMBO J 31:3079–3091CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Farin HF, Van Es JH, Clevers H (2012) Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells. Gastroenterology 143:1518–1529CrossRefPubMedGoogle Scholar
  30. 30.
    Sander GR, Powell BC (2004) Expression of notch receptors and ligands in the adult gut. J Histochem Cytochem 52:509–516CrossRefPubMedGoogle Scholar
  31. 31.
    Sancho R, Cremona CA, Behrens A (2015) Stem cell and progenitor fate in the mammalian intestine: notch and lateral inhibition in homeostasis and disease. EMBO Rep 16:571–581CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kim T-H, Escudero S, Shivdasani RA (2012) Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells. Proc Natl Acad Sic USA 109:3932–3937CrossRefGoogle Scholar
  33. 33.
    Kaemmerer E, Kuhn P, Schneider U, Jeon MK, Klaus C, Schiffer M, Weisner D, Liedtke C, Jäkel J, Kennes LN, Hilgers RD, Wagner N, Gassler N (2015) Intestinal genetic inactivation of caspase-8 diminishes migration of enterocytes. World J Gastroenterol 21:4499–4508CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Pellegrinet L, Rodilla V, Liu Z, Chen S, Koch U, Espinosa L, Kaestner KH, Kopan R, Lewis J, Radtke F (2011) Dll1- and Dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140:1230–1240CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • M. K. Jeon
    • 1
  • E. Kaemmerer
    • 1
    • 2
  • U. Schneider
    • 1
  • M. Schiffer
    • 1
  • C. Klaus
    • 1
  • J. Hennings
    • 3
  • T. Clahsen
    • 2
  • T. Ackerstaff
    • 1
  • M. Niggemann
    • 4
  • A. Schippers
    • 2
  • T. Longerich
    • 1
  • G. Sellge
    • 3
  • C. Trautwein
    • 3
  • N. Wagner
    • 2
  • C. Liedtke
    • 3
  • N. Gassler
    • 1
    • 5
  1. 1.Institute of PathologyRWTH Aachen UniversityAachenGermany
  2. 2.Department of PediatricsRWTH Aachen UniversityAachenGermany
  3. 3.Department of Medicine IIIRWTH Aachen UniversityAachenGermany
  4. 4.Institute of Organic ChemistryRWTH Aachen UniversityAachenGermany
  5. 5.Klinikum BraunschweigInstitute of PathologyBraunschweigGermany

Personalised recommendations