期刊
GASTROENTEROLOGY
卷 138, 期 4, 页码 1546-U421出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2009.12.008
关键词
Hepatitis; Innate Immunity; NOD1; CD11b
资金
- Arcir
- Conseil Regional of Nord Pas-de-Calais
- Institut de Recherches Scientifiques sur les Boissons, Paris, France, INSERM
- Institut Universitaire de France
- Agence Nationale de la Recherche [ANR-06-PHYSIO-022]
- Fonds europeen de developpement regional (FEDER)
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 (CCl4). 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 CCl4 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 kappa B were activated in Nod1(vertical bar/vertical bar) 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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