Neutrophil Migration During Liver Injury Is Under Nucleotide-Binding Oligomerization Domain 1 Control

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 κB 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.