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Lab Invest ; 92(5): 724-34, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22430509

RESUMO

Although acute liver failure is a rare disease, its presence is associated with high morbidity and mortality in affected patients. While a contribution of the immune system to the outcome of toxic liver failure is anticipated, functionally relevant immune cell receptors for liver cell damage need to be better defined. We here investigate the relevance of the chemokine receptor CXCR3, which is important for hepatic immune cell infiltration, in a model of experimental acute liver failure. Liver injury was induced by a single intraperitoneal injection of carbon tetrachloride (CCl(4)) in CXCR3(-/-), CCR1(-/-), CCR5(-/-) and wild-type mice. In this model, CXCR3(-/-) mice displayed augmented liver damage compared with all other mouse strains as assessed by liver histology and serum transaminases 24 and 72 h after injury. Phenotypically, CXCR3(-/-) mice had significantly reduced intrahepatic NK and NKT cells after injury at all investigated time points (all P<0.05), but strongly elevated expression levels of IL1-ß, TNF-α and IFN-γ. In line with a functional role of innate immune cells, wild-type mice depleted for NK cells with an anti-ASIALO GM1 antibody before liver injury also displayed increased liver injury after CCl(4) challenge. CXCR3(-/-) and NK cell-depleted mice show reduced apoptotic liver cells (TUNEL assay), but more necrotic hepatocytes. Functionally, the augmented liver cell necrosis in CXCR3(-/-) and NK cell-depleted mice was associated with increased expression of high mobility group 1 (HMGB1) protein and a consecutive enhanced infiltration of neutrophils into the liver. In conclusion, the results demonstrate a primarily unexpected beneficial role of CXCR3 in acute toxic liver injury. These findings should be taken into account when planning trials with CXCR3 antagonists.


Assuntos
Proteína HMGB1/metabolismo , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/metabolismo , Receptores CXCR3/metabolismo , Animais , Tetracloreto de Carbono/farmacologia , Proteína HMGB1/imunologia , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Receptores CCR1/imunologia , Receptores CCR1/metabolismo , Receptores CCR5/imunologia , Receptores CCR5/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Transaminases/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
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