1. ¹INSERM U795, Lille, France
2. ²Université Lille 2, Lille, France
3. ³CHRU Lille, Hôpital Huriez, Service des Maladies de l'Appareil digestif et de la Nutrition, Lille, France
4. ⁴Service d'Anatomie et de Cytologie pathologiques, AP-HP, France et Equipe d'Accueil 3102, Université Paris VII, Hôpital Robert Debré, Paris, France
5. ⁵Unité INSERM U843, Hôpital Robert Debré, AP-HP, Paris, France
6. ⁶Department of Immunology, University of Toronto, Toronto, Ontario, Canada
7. ⁷INSERM U674, Génomique fonctionnelle des Tumeurs solides, Fondation Jean Dausset-CEPH, Paris, France
8. ⁸CNRS, Unité mixte de Recherche 6543, Faculté de Sciences, Université de Sophia Antipolis, Nice, France
9. ⁹Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
10. ¹⁰Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
11. ¹¹INSERM U510 Pathogens and functions of polarized epithelial cells, Faculty of Pharmacy, University Paris XI, Châtenay-Malabry, France
12. ¹²Laboratoire de Biologie cellulaire, Université Paris V, Service de Chirurgie, Hôpital Cochin, Paris, France
13. ¹³INSERM U786 Pathogénie microbienne moléculaire, Institut Pasteur, Paris, France

Correspondence: Dr S Dharancy, MD, PhD, Service des Maladies de l'Appareil digestif et de la Nutrition, Hôpital Huriez, rue Michel Polonowski, CHU, Lille 59037, France. E-mail: s6@chru-lille.fr

¹⁴These authors contributed equally to this work.

Received 7 September 2007; Revised 6 November 2007; Accepted 20 November 2007; Published online 28 January 2008.

Abstract

The recent discovery of bacterial receptors such as NOD2 that contribute to crosstalk between innate and adaptive immune systems in the digestive tract constitutes an important challenge in our understanding of liver injury mechanisms. The present study focuses on NOD2 functions during liver injury. NOD2, TNF- and IFN- mRNA were quantified using real-time PCR in liver samples from patients and mice with liver injury. We evaluated the susceptibility of concanavalin A (ConA) challenge in NOD2-deficient mice (Nod2^-/-) compared to wild-type littermates. We tested the effect of muramyl dipeptide (MDP), the specific activator of NOD2, on ConA-induced liver injury in C57BL/6 mice. We studied the cellular distribution and the role of NOD2 in immune cells and hepatocytes. We demonstrated that NOD2, TNF- and IFN- were upregulated during liver injury in mice and humans. Nod2^-/- mice were resistant to ConA-induced hepatitis compared to their wild-type littermates, through reduced IFN- production by immune cells. Conversely, administration of MDP exacerbated ConA-induced liver injury. MDP was a strong inducer of IFN- in freshly isolated human PBMC, splenocytes and hepatocytes. Our study supports the hypothesis that NOD2 contributes to liver injury via a regulatory mechanism affecting immune cells infiltrating the liver and hepatocytes. Taken together, our results indicate that NOD2 may represent a new therapeutic target in liver diseases.