Basic—Liver, Pancreas, and Biliary TractNeutrophil Migration During Liver Injury Is Under Nucleotide-Binding Oligomerization Domain 1 Control
Section snippets
Migration Assays
Random and directed migration of PMNs was studied using the Boyden chamber technique as previously described.20 N-formyl-methionyl-leucyl-phenylalanine (fMLP) was purchased from Sigma (Sigma-Aldrich, Saint-Quentin Fallavier, France). Forty-five microliters of a suspension of 1 × 106 PMNs in Hank's balanced salt solution (HBSS) containing 0.5% bovine serum albumin were incubated in the upper compartment of a chamber separated from the lower compartment by a cellulose filter (3-μm–diameter pores;
Nod1−/− Mice Displayed Impaired Hepatic PMN Recruitment
Challenge with CCl4 induced acute hepatitis with an increase in mice plasma ALT levels that peaked, as expected, at 18 hours after injection (Supplementary Figure 1). Nod1−/− and Nod1+/+ mice displayed similar kinetics of plasma ALT. Likewise, there was no difference in terms of macroscopic appearance of excised livers between the 2 groups of mice (Supplementary Figure 1). As expected, microscopic analysis of excised liver showed extensive hepatocyte necrosis in pericentrilobular areas (Figure 1
Discussion
Progress in our understanding of the mechanisms of neutrophil function is necessary to design new therapeutic approaches for patients with PMN-mediated liver injury. In the present study, we showed that NOD1 is an intrinsic central regulator of PMN migration and phagocytic capacity. In such cells, NOD1 acted, at least in part, through activation of MAPKs and NF-κB, and expression of β2 integrins at the PMN surface.
It has been shown that NOD1 indirectly influenced PMN recruitment in intestinal
Acknowledgments
S.D. and M.B.-M. contributed equally to this work.
The authors thank Nathalie Jouy for her help in flow cytometry analysis and the “Service Commun de Cytométrie et de Tri Cellulaire” set-up by Institut Fédératif de Recherche 114 (Institut de Medecine Prédictive et de Recherche Thérapeutique). The authors are grateful to Candice Duburque for valuable technical help and Aurore Saudemont for hematologic analysis. The authors thank Professor Daniel Poulain for critical reading of the manuscript. For
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Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by French grants from Arcir (from the “Conseil Regional of Nord Pas-de-Calais”), Institut de Recherches Scientifiques sur les Boissons, Paris, France, INSERM “ATC Alcool,” the “Institut Universitaire de France,”“Agence Nationale de la Recherche”ANR-06-PHYSIO-022, and Fonds européen de développement régional (FEDER).