CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice

• Published in: Hepatology (Baltimore, Md.) Vol. 42; no. 4; pp. 854 - 862
• Main Authors: MORENO, Christophe, GUSTOT, Thierry, NICAISE, Charles, QUERTINMONT, Eric, NAGY, Nathalie, PARMENTIER, Marc, LE MOINE, Olivier, DEVIERE, Jacques, LOUIS, Hubert
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01.10.2005
• Subjects: Animals; Biological and medical sciences; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - immunology; Chemical and Drug Induced Liver Injury - pathology; Chemokine CCL3; Chemokine CCL4; Chemokines, CC - metabolism; Concanavalin A; Female; Gastroenterology. Liver. Pancreas. Abdomen; Human viral diseases; Infectious diseases; Interferon-gamma - metabolism; Interleukin-4 - metabolism; Ligands; Liver - immunology; Liver - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Macrophage Inflammatory Proteins - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Other diseases. Semiology; Receptors, CCR5 - genetics; Receptors, CCR5 - immunology; Receptors, CCR5 - metabolism; Severity of Illness Index; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor Necrosis Factor-alpha - metabolism; Viral diseases; Viral hepatitis; T cell receptor; Deficiency; Rodentia; Hepatic disease; Necrosis; Infection; CCR5 chemokine receptor; Viral hepatitis A; Hepatitis; Vertebrata; Mammalia; Mouse; Viral disease; Animal; Gastroenterology; Digestive diseases; Tumor
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.20865

Experimental T-cell-mediated hepatitis induced by concanavalin A (Con A) involves the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands (CCL3, CCL4, and CCL5) regulate leukocyte chemotaxis and activation, we investigated the role of CCR5 during Con A-induced liver injury. Serum levels of CCR5 ligands and their hepatic transcript levels were significantly increased after Con A injection, whereas CCR5+ liver mononuclear cells were recruited to the liver. CCR5-deficient (CCR5-/-) mice disclosed increased mortality and liver injury following Con A administration compared with wild-type mice. CCR5-/- mice also exhibited increased production of interleukin 4, tumor necrosis factor alpha, CCL3, CCL4, and CCL5, and a prominent liver mononuclear cell infiltrate, among which many cells were CCR1+. In vivo neutralization of CCR5 ligands in CCR5-/- mice afforded a protection against hepatitis only when CCL5 was neutralized. In conclusion, CCR5 deficiency exacerbates T-cell-mediated hepatitis, and leads to increased levels of CCR5 ligands and a more pronounced liver mononuclear infiltrate, suggesting that CCR5 expression can modulate severity of immuno-mediated liver injury.