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Cell and Tissue Research

, Volume 332, Issue 2, pp 185–194 | Cite as

Anatomical evidence for ileal Peyer’s patches innervation by enteric nervous system: a potential route for prion neuroinvasion?

  • Roberto ChiocchettiEmail author
  • Gemma Mazzuoli
  • Valeria Albanese
  • Maurizio Mazzoni
  • Paolo Clavenzani
  • Giovanna Lalatta-Costerbosa
  • Maria L. Lucchi
  • Giovanni Di Guardo
  • Giuseppe Marruchella
  • John B. Furness
Regular Article

Abstract

We have examined the innervation of the gut-associated lymphoid system of the sheep ileum, with a view to identifying potential sites for neuroinvasion by pathogens, such as prions (PrPSc). Special attention has been paid to the follicles of Peyer’s patches (PPs), which are major sites of PrPSc accumulation during infection. Evidence exists that the enteric nervous system, together with the parasympathetic and sympathetic pathways projecting to the intestine, are important for PrPSc entry into the central nervous system. Thus, PrPSc might move from PPs to the neurons and nerve fibres that innervate them. We investigated, by immunohistochemistry and retrograde tracing (DiI) from the follicles, the distribution and phenotype of enteric neurons innervating the follicles. Antibodies against protein gene product 9.5, tyrosine hydroxylase, dopamine β hydroxylase, choline acetyltransferase, calbindin (CALB), calcitonin gene-related peptide (CGRP), and nitric oxide synthase were used to characterise the neurons. Immunoreactivity for each of these was observed in fibres around and inside PP follicles. CGRP-immunoreactive fibres were mainly seen at the follicular dome. Retrograde tracing revealed submucosal neurons that contributed to the innervation of PPs, including Dogiel type II neurons and neurons immunoreactive for CALB and CGRP. The major source of the adrenergic fibres are the sympathetic ganglia. Our results thus suggest that enteric and sympathetic neurons are involved during the first stage of neuroinvasion, with neurons connecting to them acting as potential carriers of PrPSc to the central nervous system.

Keywords

Intestinal immune system Enteric nervous system Peyer’s patches DiI Prion diseases Sheep 

Notes

Acknowledgements

The careful technical assistance of Caterina Mongardi-Fantaguzzi is gratefully acknowledged.

References

  1. Aguzzi A, Heikenwalder M (2006) Pathogenesis of prion diseases: current status and future outlook. Nat Rev Microbiol 4:765–775PubMedCrossRefGoogle Scholar
  2. Aguzzi A, Polymenidou M (2004) Mammalian prion biology: one century of evolving concepts. Cell 116:313–327PubMedCrossRefGoogle Scholar
  3. Balemba OB, Mbassa GK, Semuguruka WD, Assey RJ, Kahwa CK, Hay-Schmidt A, Dantzer V (1999) The topography, architecture and structure of the enteric nervous system in the jejunum and ileum of cattle. J Anat 195:1–9PubMedCrossRefGoogle Scholar
  4. Beekes M, McBride PA (2007) The spread of prions through the body in naturally acquired transmissible spongiform encephalopathies. FEBS J 274:588–605PubMedCrossRefGoogle Scholar
  5. Bienenstock J, Croitoru K, Ernst PB, Stead RH, Stanisz A (1989) Neuroendocrine regulation of mucosal immunity. Immunol Invest 18:69–76PubMedCrossRefGoogle Scholar
  6. Brehmer A, Schrödl F, Neuhuber W, Tooyama I, Kimura H (2006) Co-expression pattern of neuronal nitric oxide synthase and two variants of choline acetyltransferase in myenteric neurons of porcine ileum. J Chem Neuroanat 27:33–41CrossRefGoogle Scholar
  7. Carucci JA, Ignatius R, Wei Y, Cypess AM, Schaer DA, Pope M, Steinman RM, Mojsov S (2000) Calcitonin gene-related peptide decreases expression of HLA-DR and CD86 by human dendritic cells and dampens dendritic cell-driven T cell-proliferative responses via the type I calcitonin gene-related peptide receptor. J Immunol 164:3494–3499PubMedGoogle Scholar
  8. Chiocchetti R, Grandis A, Bombardi C, Clavenzani P, Lalatta-Costerbosa G, Lucchi ML, Furness JB (2004) Characterisation of neurons expressing calbindin immunoreactivity in the ileum of the unweaned and mature sheep. Cell Tissue Res 318:289–303PubMedCrossRefGoogle Scholar
  9. Chiocchetti R, Clavenzani P, Mazzoni M, Albanese V, Di Guardo G, De Grossi L, Bortolami R, Lalatta-Costerbosa G (2005) The sheep enteric nervous system after scrapie (PrPSc) infection. Autonomic Neurosci 119:144–145Google Scholar
  10. Chiocchetti R, Grandis A, Bombardi C, Lucchi ML, Tadini Dal Lago D, Bortolami R, Furness JB (2006) Extrinsic and intrinsic sources of calcitonin gene-related peptide immunoreactivity in the lamb ileum. A morphometric and neurochemical investigation. Cell Tissue Res 323:183–196PubMedCrossRefGoogle Scholar
  11. Defaweux V, Dorban G, Demonceau C, Piret J, Jolois O, Thellin O, Thielen C, Heinen E, Antoine N (2005) Interfaces between dendritic cells, other immune cells, and nerve fibres in mouse Peyer’s patches: potential sites for neuroinvasion in prion diseases. Microsc Res Tech 6:1–9CrossRefGoogle Scholar
  12. Defaweux V, Dorban G, Antoine N, Piret J, Gabriel A, Jacqmot O, Falisse-Poirier N, Flandroy S, Zorzi D, Heinen E (2007) Neuroimmune connections in jejunal and ileal Peyer’s patches at various bovine ages: potential sites for prion neuroinvasion. Cell Tissue Res 329:35–44PubMedCrossRefGoogle Scholar
  13. Driessen A, Creemers J, Gebos K (1992) The innervation of the lymphoid tissue at the ileocolonic transition: an enzyme and immunohistochemical study. Acta Anat (Basel) 144:304–310Google Scholar
  14. Falck B, Nystedt T, Rosengren E, Stenflo J (1964) Dopamine and mast cells in ruminants. Acta Pharmacol Toxicol 21:51–58CrossRefGoogle Scholar
  15. Feher E, Fodor M, Burnstock G (1992) Distribution of somatostatin-immunoreactive nerve fibres in Peyer’s patches. Gut 33:1195–1198PubMedCrossRefGoogle Scholar
  16. Felten DL, Felten SY, Carlson SL, Olschowaka JA, Livnat S (1985) Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol 135:755S–765SPubMedGoogle Scholar
  17. Felten DL, Felten SY, Bellinger DL, Carlson SL, Ackerman KD, Madden KS, Olschowki JA, Livnat S (1987) Noradrenergic sympathetic neural interactions with the immune system. Structure and function. Immunol Rev 100:225–260PubMedCrossRefGoogle Scholar
  18. Felten SY, Felten DL, Bellinger DL, Carlson SL, Ackerman KD, Madden KS, Olschowka JA, Livnat S (1988) Noradrenergic sympathetic innervation of lymphoid organs. Prog Allergy 43:14–36PubMedGoogle Scholar
  19. Freeman JG, Ryan JJ, Shelburne CP, Bailey DP, Bouton AL, Narasimhachari N, Domen J, Siméon N, Couderc F, Stewart JK (2001) Catecholamines in murine bone marrow derived mast cells. J Neuroimmunol 119:231–238PubMedCrossRefGoogle Scholar
  20. Furness JB (2006) The enteric nervous system. Blackwell, Oxford, pp 64–66Google Scholar
  21. Furness JB, Robbins HL, Xiao J, Stebbing MJ, Nurgali K (2004)Projections and chemistry of Dogiel type II neurons in the mouse colon.Cell Tissue Res 317:1–12PubMedCrossRefGoogle Scholar
  22. Gerber HA, Morris B, Trevella W (1986) The role of gut-associated lymphoid tissues in the generation of immunoglobulin-bearing lymphocytes in sheep. Aust J Exp Biol Med Sci 64:201–203PubMedCrossRefGoogle Scholar
  23. Glatzel M, Heppner FL, Albers KM, Aguzzi A (2001) Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31:25–34PubMedCrossRefGoogle Scholar
  24. Gonzales-Ariki S, Husband AJ (2000) Ontogeny of IgA+ cells in lamina propria: effects of sympathectomy. Dev Comp Immunol 24:61–69CrossRefGoogle Scholar
  25. Goode T, O’Connell J, Ho WZ, O’Sullivan GC, Collins JK, Douglas SD, Shanahan F (2000) Differential expression of neurokinin-1 receptor by human mucosal and peripheral lymphoid cells. Clin Diagn Lab Immunol 7:371–376PubMedCrossRefGoogle Scholar
  26. Green T, Dockray GJ (1987) Calcitonin gene-related peptide and substance P in afferents to the upper gastrointestinal tract in the rat. Neurosci Lett 76:151–156PubMedCrossRefGoogle Scholar
  27. Green BT, Lyte M, Kulkarni-Narla A, Brown DR (2003) Neuromodulation of enteropathogen internalization in Peyer’s patches from porcine jejunum. J Neuroimmunol 141:74–78PubMedCrossRefGoogle Scholar
  28. Haïk S, Faucheux BA, Sazdovitch V, Privat N, Kemeny JL, Perret-Liaudet A, Hauw JJ (2003) The sympathetic nervous system is involved in variant Creutzfeldt-Jakob disease. Nat Med 9:1121–1129PubMedCrossRefGoogle Scholar
  29. Heggebø R, Gonzales L, Press CM, Gunnes G, Espenes A, Jeffrey M (2003) Disease associated PrP in the enteric nervous system of scrapie-affected sheep. J Gen Virol 84:1327–1338PubMedCrossRefGoogle Scholar
  30. Hens J, Schrödl F, Brehmer A, Adriaensen D, Neuhuber W, Scheuermann DW, Schemann M, Timmermans JP (2000) Mucosal projections of enteric neurons in the porcine small intestine. J Comp Neurol 421:429–436PubMedCrossRefGoogle Scholar
  31. Hens J, Vanderwinden JM, De Laet MH, Scheuermann DW, Timmermans JP (2001)Morphological and neurochemical identification of enteric neurones with mucosal projections in the human small intestine. J Neurochem 76:464-471PubMedCrossRefGoogle Scholar
  32. Heppner FL, Christ AD, Klein MA, Prinz M, Fried M, Kraehenbuhl JP, Aguzzi A (2001) Transepithelial prion transport by M cells. Nat Med 7:976–977PubMedCrossRefGoogle Scholar
  33. Holzer P, Wachter C, Heinemann A, Jocic M, Lippe IT, Herbert MK (1995) Diverse interactions of calcitonin gene related peptide and nitric oxide in the gastric and cutaneous microcirculation. Can J Physiol Pharmacol 73:991–994PubMedGoogle Scholar
  34. Huntley JF, Haig DM, Irvine J, Inglis L, MacDonald A, Rance A, Moqbel R (1992) Characterisation of ovine mast cells derived from in vitro culture of haemopoietic tissue. Vet Immunol Immunopathol 32:47–64PubMedCrossRefGoogle Scholar
  35. Ichikawa S, Sreedharan SP, Goetzl EJ, Owen RL (1994) Immunohistochemical localization of peptidergic nerve fibres and neuropeptide receptors in Peyer’s patches of the cat ileum. Regul Pept 54:385-395PubMedCrossRefGoogle Scholar
  36. Krammer HJ, Kühnel W (1993) Topography of the enteric nervous system in Peyer’s patches of the porcine small intestine. Cell Tissue Res 272:267–272PubMedCrossRefGoogle Scholar
  37. Kulkarni-Narla A, Beitz AJ, Brown DR (1999) Catecholaminergic, cholinergic and peptidergic innervation of gut-associated lymphoid tissue in porcine jejunum and ileum. Cell Tissue Res 298:275–286PubMedCrossRefGoogle Scholar
  38. Lalatta-Costerbosa G, Mazzoni M, Clavenzani P, Di Guardo G, Mazzuoli G, Marruchella G, De Grossi L, Agrimi U, Chiocchetti R (2007) NOS-immunoreactivity and NADPH-d histochemistry in the enteric nervous system of Sarda breed sheep with different PrP genotypes in wholemount and cryostat preparations. J Histochem Cytochem 55:387–401PubMedCrossRefGoogle Scholar
  39. Landsverk T, Halleraker M, Aleksandersen M, McClure S, Hein W, Nicander L (1991) The intestinal habitat for organized lymphoid tissues in ruminants; comparative aspects of structure, function and development. Vet Immunol Immunopathol 28:1–16PubMedCrossRefGoogle Scholar
  40. Ma B, Wasielewski R von, Lindenmaier W, Dittmar KEJ (2007) Immmunohistochemical study of the blood and lymphatic vasculature and the innervation of mouse gut and gut-associated lymphoid tissue. Anat Histol Embryol 36:62–74PubMedCrossRefGoogle Scholar
  41. Mabbott NA, MacPherson GG (2006) Prions and their lethal journey to the brain. Nat Rev Microbiol 4:201–211PubMedCrossRefGoogle Scholar
  42. Mao Y, Wang B, Kunze W (2006) Characterization of myenteric sensory neurons in the mouse small intestine. J Neurophysiol 96:998–1010PubMedCrossRefGoogle Scholar
  43. Marruchella G, Ligios C, Albanese V, Cancedda MG, Madau L, Lalatta-Costerbosa G, Mazzoni M, Clavenzani P, Chiocchetti R, Sarli G, De Grossi L, Agrimi U, Aguzzi A, Di Guardo G (2007) Enteroglia and neuron involvement without apparent neuronal loss in ileal enteric nervous system plexi from scrapie-affected sheep. J Gen Virol 88:2899–2904PubMedCrossRefGoogle Scholar
  44. Mazzuoli G, Mazzoni M, Albanese V, Clavenzani P, Lalatta-Costerbosa G, Lucchi ML, Furness JB, Chiocchetti R (2007) Morphology and neurochemistry of descending and ascending myenteric plexus neurons of sheep ileum. Anat Rec 290:1480–1491CrossRefGoogle Scholar
  45. Ottaway CA, Lewis DL, Asa SL (1987) Vasoactive intestinal peptide-containing nerves in Peyer’s patches. Brain Behav Immun 1:148–158PubMedCrossRefGoogle Scholar
  46. Pascual DW, Kiyono H, McGhee JR (1994) The enteric nervous system: interactions for mucosal immunity and inflammation. Immunomethods 5:56–72PubMedCrossRefGoogle Scholar
  47. Payan DG, McGillis JP, Renold FK, Mitsuhashi M, Goetzl EJ (1987) Neuropeptide modulation of leukocyte function. Ann N Y Acad Sci 496:182–191PubMedCrossRefGoogle Scholar
  48. Pfannkuche H, Schemann M, Gäbel G (2002) Ruminal muscle of sheep is innervated by non-polarized pathways of cholinergic and nitrergic myenteric neurones. Cell Tissue Res 309:347–354PubMedCrossRefGoogle Scholar
  49. Pfoch M, Unsicker K (1972) Electron microscopic study on the innervation of Peyer’s patches of the Syrian hamster. Z Zellforsch Mikrosk Anat 123:425–429PubMedCrossRefGoogle Scholar
  50. Powley TL (2000) Vagal input to the enteric nervous system. Gut 47:iv30–iv32PubMedCrossRefGoogle Scholar
  51. Press CM, Heggebø R, Espenes A (2004) Involvement of gut-associated lymphoid tissue of ruminants in the spread of transmissible spongiform encephalopathies. Adv Drug Deliv Rev 56:885–899PubMedCrossRefGoogle Scholar
  52. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383PubMedCrossRefGoogle Scholar
  53. Reynaud CA, Mackay CR, Muller RG, Weill JC (1991) Somatic generation of diversity in a mammalian primary lymphoid organ: the sheep ileal Peyer’s patches. Cell 64:995–1005PubMedCrossRefGoogle Scholar
  54. Sharkey KA (1992) Substance P and calcitonin gene-related peptide (CGRP) in gastrointestinal inflammation. Ann N Y Acad Sci 664:425–442PubMedCrossRefGoogle Scholar
  55. Sharkey KA, Lomax AEG, Bertrand PP, Furness JB (1998) Electrophysiology, shape and chemistry of intestinofugal neurons projecting from guinea pig distal colon to inferior mesenteric ganglia. Gastroenterology 115:909–918PubMedCrossRefGoogle Scholar
  56. Shtylik AV, Otellin VA, Nozdrachev AD (1998) Innervation of grouped lymphoid nodules (Peyer’s patches) by the enteric nervous system and the topography of their interior neural elements in the rat. Morfologiia 114:34–39PubMedGoogle Scholar
  57. Stead RH (1992) Innervation of mucosal immune cells in the gastrointestinal tract. Reg Immunol 4:91–99PubMedGoogle Scholar
  58. Tooyama I, Kimura H (2000) A protein encoded by an alternative splice variant of choline acetyltransferase mRNA is localized preferentially in peripheral nerve cells and fibers. J Chem Neuroanat 17:217–226PubMedCrossRefGoogle Scholar
  59. Vulchanova L, Casey MA, Crabb GW, Kennedy WR, Brown DR (2007) Anatomical evidence for enteric neuroimmune interactions in Peyer’s patches. J Neuroimmunol 185:64–74PubMedCrossRefGoogle Scholar
  60. Yamaguchi K, Schoefl GI (1983) Blood vessels of the Peyer’s patches in the mouse. I. Topographical studies. Anat Rec 206:391–401PubMedCrossRefGoogle Scholar
  61. Young HM, Anderson CR, Furness JB (2000) Nitric oxide in the peripheral autonomic nervous system. In: Steinbusch HWM, De Vente J, Vincent SR, Björklund A, Hökfelt T (eds) Handbook of chemical neuroanatomy, vol 17. Elsevier Science, Amsterdam, pp 215–226Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Roberto Chiocchetti
    • 1
    Email author
  • Gemma Mazzuoli
    • 1
  • Valeria Albanese
    • 2
    • 3
  • Maurizio Mazzoni
    • 1
  • Paolo Clavenzani
    • 1
  • Giovanna Lalatta-Costerbosa
    • 1
  • Maria L. Lucchi
    • 1
  • Giovanni Di Guardo
    • 2
  • Giuseppe Marruchella
    • 2
  • John B. Furness
    • 3
  1. 1.Department of Veterinary Morphophysiology and Animal ProductionsUniversity of BolognaBolognaItaly
  2. 2.Department of Comparative Biomedical SciencesUniversity of TeramoTeramoItaly
  3. 3.Department of Anatomy and Cell BiologyUniversity of MelbourneParkvilleAustralia

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