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Enteric glia protect against Shigella flexneri invasion in intestinal epithelial cells: a role for S-nitrosoglutathione
  1. Mathurin Flamant1,2,3,
  2. Philippe Aubert1,2,3,
  3. Malvyne Rolli-Derkinderen4,
  4. Arnaud Bourreille1,2,3,
  5. Margarida Ribeiro Neunlist1,2,3,
  6. Maxime M Mahé1,2,3,
  7. Guillaume Meurette1,2,
  8. Benoit Marteyn5,
  9. Tor Savidge6,
  10. Jean Paul Galmiche1,2,3,
  11. Philippe J Sansonetti5,
  12. Michel Neunlist1,2,3
  1. 1INSERM, UMR 913, Nantes, France
  2. 2CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, Nantes, France
  3. 3Université de Nantes, Faculté de Médecine, Nantes, France
  4. 4INSERM, UMR 915, Nantes, France
  5. 5Unité de Pathogénie Microbienne Moléculaire & Unité INSERM 786, Institut Pasteur, Paris, France
  6. 6University Texas Medical Branch (UTMB), Department of Gastroenterology, Galveston, Texas, USA
  1. Correspondence to Dr Michel Neunlist, INSERM U913, Place Alexis Ricordeau, 44035 Nantes Cedex, France; michel.neunlist{at}univ-nantes.fr

Abstract

Background Enteric glial cells (EGCs) are important regulators of intestinal epithelial barrier (IEB) functions. EGC-derived S-nitrosoglutathione (GSNO) has been shown to regulate IEB permeability. Whether EGCs and GSNO protect the IEB during infectious insult by pathogens such as Shigella flexneri is not known.

Methods S flexneri effects were characterised using in vitro coculture models of Caco-2 cells and EGCs (or GSNO), ex vivo human colonic mucosa, and in vivo ligated rabbit intestinal loops. The effect of EGCs on S flexneri-induced changes in the invasion area and the inflammatory response were analysed by combining immunohistochemical, ELISA and PCR methods. Expression of small G-proteins was analysed by western blot. Expression of ZO-1 and localisation of bacteria were analysed by fluorescence microscopy.

Results EGCs significantly reduced barrier lesions and inflammatory response induced by S flexneri in Caco-2 monolayers. The EGC-mediated effects were reproduced by GSNO, but not by reduced glutathione, and pharmacological inhibition of pathways involved in GSNO synthesis reduced EGC protecting effects. Furthermore, expression of Cdc42 and phospho-PAK in Caco-2 monolayers was significantly reduced in the presence of EGCs or GSNO. In addition, changes in ZO-1 expression and distribution induced by S flexneri were prevented by EGCs and GSNO. Finally, GSNO reduced S flexneri-induced lesions of the IEB in human mucosal colonic explants and in a rabbit model of shigellosis.

Conclusion These results highlight a major protective function of EGCs and GSNO in the IEB against S flexneri attack. Consequently, this study lays the scientific basis for using GSNO to reduce barrier susceptibility to infectious or inflammatory challenge.

  • Enteric nervous system
  • enteric glial cells
  • intestinal infection
  • Shigella flexneri
  • infectious disease
  • nerve - gut interactions

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Footnotes

  • See Commentary, p 429

  • Linked articles 231019.

  • Funding MF was supported by a master fellowship from Sanofi-Aventis and was the recipient of an IRMAD Astra-Zeneca grant. Part of this work was also supported by a grant from INCA ‘Appel à projets libres 2007’. TS was supported by Eli Broad Foundation and National Institutes of Health (1R21DK078032). M R-D. is funded by the Centre National de la Recherche Scientifique (CNRS).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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