Nucleotide-binding oligomerization domain 1 (NOD1) modulates liver ischemia reperfusion through the expression adhesion molecules

• Published in: Journal of hepatology 2019-06, Vol.70 (6), p.1159-1169
• Main Authors: Lassailly, Guillaume, Bou Saleh, Mohamed, Leleu-Chavain, Natascha, Ningarhari, Massih, Gantier, Emilie, Carpentier, Rodolphe, Artru, Florent, Gnemmi, Viviane, Bertin, Benjamin, Maboudou, Patrice, Betbeder, Didier, Gheeraert, Céline, Maggiotto, François, Dharancy, Sébastien, Mathurin, Philippe, Louvet, Alexandre, Dubuquoy, Laurent
• Format: Article
• Language: English
• Subjects: Adhesion molecules; Agonists; Cell adhesion molecules; Cell culture; Dehydrogenases; Electron microscopy; Endothelial cells; Endothelium; Hepatocytes; Innate immunity; Intercellular adhesion molecule 1; Ischemia; L-Lactate dehydrogenase; Lactic acid; Leukocytes (polymorphonuclear); Life Sciences; Liver; Liver ischemia reperfusion; Liver transplantation; Lysis; Microscopy; Nanoparticles; Nanoparticles antagonist; Nod1 protein; Oligomerization; Reperfusion; Vascular cell adhesion molecule 1
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2019.01.019

[Display omitted] •NOD1 agonists induced expression of adhesion molecules in the normal and IR-injured livers.•NOD1 mediates interactions between hepatocytes and polymorphonuclear neutrophils during liver IR.•Insoluble NOD1 inhibitors were efficiently integrated into PLGA nanoparticles for use in vivo.•NOD1 antagonist nanoparticles reduced ICAM-1 expression and IR-induced liver injury.•The NOD1 pathway modulates liver IR injury by targeting polymorphonuclear neutrophil function and adhesion molecules. In liver transplantation, organ shortage leads to the use of marginal grafts that are more susceptible to ischemia–reperfusion (IR) injury. We identified nucleotide-binding oligomerization domain 1 (NOD1) as an important modulator of polymorphonuclear neutrophil (PMN)-induced liver injury, which occurs in IR. Herein, we aimed to elucidate the role of NOD1 in IR injury, particularly focusing on its effects on the endothelium and hepatocytes. Nod1 WT and KO mice were treated with NOD1 agonists and subjected to liver IR. Expression of adhesion molecules was analyzed in total liver, isolated hepatocytes and endothelial cells. Interactions between PMNs and hepatocytes were studied in an ex vivo co-culture model using electron microscopy and lactate dehydrogenase levels. We generated NOD1 antagonist-loaded nanoparticles (np ALINO). NOD1 agonist treatment increased liver injury, PMN tissue infiltration and upregulated ICAM-1 and VCAM-1 expression 20 hours after reperfusion. NOD1 agonist treatment without IR increased expression of adhesion molecules (ICAM-1, VCAM-1) in total liver and more particularly in WT hepatocytes, but not in Nod1 KO hepatocytes. This induction is dependent of p38 and ERK signaling pathways. Compared to untreated hepatocytes, a NOD1 agonist markedly increased hepatocyte lysis in co-culture with PMNs as shown by the increase of lactate dehydrogenase in supernatants. Interaction between hepatocytes and PMNs was confirmed by electron microscopy. In a mouse model of liver IR, treatment with np ALINO significantly reduced the area of necrosis, aminotransferase levels and ICAM-1 expression. NOD1 regulates liver IR injury through induction of adhesion molecules and modulation of hepatocyte-PMN interactions. NOD1 antagonist-loaded nanoparticles reduced liver IR injury and provide a potential approach to prevent IR, especially in the context of liver transplantation. Nucleotide-binding oligomerization domain 1 (NOD1) is as an important modulator of pol