CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice.
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.
Moreno
Christophe
C
Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium. cmoreno@ulb.ac.be
Gustot
Thierry
T
Nicaise
Charles
C
Quertinmont
Eric
E
Nagy
Nathalie
N
Parmentier
Marc
M
Le Moine
Olivier
O
Devière
Jacques
J
Louis
Hubert
H
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000378:metabolism; D003208:Concanavalin A; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000276:immunology / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019713:Receptors, CCR5 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C496534:Ccl3 protein, mouse; C496535:Ccl4 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D015847:Interleukin-4; D007371:Interferon-gamma