Neutrophil migration during liver injury is under nucleotide-binding oligomerization domain 1 control.
OBJECTIVE
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.
Dharancy
Sébastien
S
INSERM U995, Lille, France.
Body-Malapel
Mathilde
M
Louvet
Alexandre
A
Berrebi
Dominique
D
Gantier
Emilie
E
Gosset
Philippe
P
Viala
Jérôme
J
Hollebecque
Antoine
A
Moreno
Christophe
C
Philpott
Dana J
DJ
Girardin
Stephen E
SE
Sansonetti
Philippe J
PJ
Desreumaux
Pierre
P
Mathurin
Philippe
P
Dubuquoy
Laurent
L
D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D002465:Cell Movement; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D008099:Liver / Q000098:blood supply / Q000276:immunology; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D053474:Nod1 Signaling Adaptor Protein / Q000502:physiology*; D015427:Reperfusion Injury / Q000209:etiology
D039481:CD11b Antigen; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse