| 20026116 |
Dharancy S, Body-Malapel M, Louvet A, Berrebi D, Gantier E, Gosset P, Viala J, Hollebecque A, Moreno C, Philpott DJ, Girardin SE, Sansonetti PJ, Desreumaux P, Mathurin P, Dubuquoy L: Neutrophil migration during liver injury is under nucleotide-binding oligomerization domain 1 control. Gastroenterology. 2010 Apr;138(4):1546-56
BACKGROUND & AIMS: A more complete understanding of the mechanisms involved in pathogen-associated molecular pattern signaling is crucial in the setting of liver injury. In intestinal diseases, nucleotide-binding oligomerization domain 1 (NOD1), a receptor for bacteria, appears to regulate cross-talk between innate and adaptive immunity, involving polymorphonuclear neutrophils (PMNs). Our aim was to explore the role of NOD1 in PMN-induced liver injury. METHODS: Nod1 (+/+) and Nod1 (-/-) mice were challenged with carbon tetrachloride (CCl (4)). Migration and phagocytosis of Nod1 (+/+) and Nod1 (-/-) PMN were studied in vivo and ex vivo. We evaluated main inflammatory pathways in PMNs by Western blot and CD11b expression using fluorescence-activated cell sorting. Mice were submitted to liver ischemia/reperfusion. RESULTS: After CCl (4) exposure, livers of Nod1 (-/-) mice had more than 50% less PMN infiltration within necrotic areas than those of Nod1 (+/+). PMNs isolated from Nod1 (-/-) mice displayed a 90% decrease in migration capacity compared with Nod1 (+/+) PMNs, whereas FK 565, a potent NOD1 ligand, increased PMN migration. Upon FK 565 stimulation, mitogen-activated protein kinase and nuclear factor kappaB were activated in Nod1 (+/+) PMNs, but less so in Nod1 (-/-) PMNs. Expression of CD11b on the Nod1 (-/-) PMN was decreased compared with Nod1 (+/+). The phagocytic capacity of Nod1 (-/-) PMNs was decreased by more than 50% compared with Nod1 (+/+). In an ischemia/reperfusion model of PMN-induced liver injury, FK 565 increased lesions, whereas Nod1 (-/-) mice were protected. CONCLUSIONS: The identification of NOD1 as a modulator of PMN function and migration in the liver suggests that this receptor may represent a new therapeutic target in PMN-dependent liver diseases. |
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