TY - JOUR
T1 - CCR5 and CXCR3 are dispensable for liver infiltration, but CCR5 protects against virus-induced T-cell-mediated hepatic steatosis
AU - Holst, P J
AU - Orskov, C
AU - Qvortrup, K
AU - Christensen, Jan Pravsgaard
AU - Thomsen, Allan Randrup
N1 - Keywords: Animals; Arenaviridae Infections; Autoimmunity; CD8-Positive T-Lymphocytes; Cell Movement; Chemokines; Fatty Liver; Inflammation; Lymphocytic choriomeningitis virus; Mice; Mice, Knockout; Receptors, CCR5; Receptors, CXCR3; Receptors, Chemokine
PY - 2007
Y1 - 2007
N2 - CCR5 and CXCR3 are important molecules in regulating the migration of activated lymphocytes. Thus, the majority of tissue-infiltrating T cells found in the context of autoimmune conditions and viral infections express CCR5 and CXCR3, and the principal chemokine ligands are expressed within inflamed tissues. Accordingly, intervention studies have pointed to nonredundant roles of these receptors in models of allograft rejection, viral infection, and autoimmunity. In spite of this, considerable controversy exists, with many studies failing to support a role for CCR5 or CXCR3 in disease pathogenesis. One possible explanation is that different chemokine receptors may take over in the absence of any individual receptor, thus rendering individual receptors redundant. We have attempted to address this issue by analyzing CCR5(-/-), CXCR3(-/-), and CCR5/CXCR3(-/-) mice with regard to virus-induced liver inflammation, generation and recruitment of effector cells, virus control, and immunopathology. Our results indicate that CCR5 and CXCR3 are largely dispensable for tissue infiltration and virus control. In contrast, the T-cell response is accelerated in CCR5(-/-) and CCR5/CXCR3(-/-) mice and the absence of CCR5 is associated with the induction of CD8(+) T-cell-mediated immunopathology consisting of marked hepatic microvesicular steatosis.
AB - CCR5 and CXCR3 are important molecules in regulating the migration of activated lymphocytes. Thus, the majority of tissue-infiltrating T cells found in the context of autoimmune conditions and viral infections express CCR5 and CXCR3, and the principal chemokine ligands are expressed within inflamed tissues. Accordingly, intervention studies have pointed to nonredundant roles of these receptors in models of allograft rejection, viral infection, and autoimmunity. In spite of this, considerable controversy exists, with many studies failing to support a role for CCR5 or CXCR3 in disease pathogenesis. One possible explanation is that different chemokine receptors may take over in the absence of any individual receptor, thus rendering individual receptors redundant. We have attempted to address this issue by analyzing CCR5(-/-), CXCR3(-/-), and CCR5/CXCR3(-/-) mice with regard to virus-induced liver inflammation, generation and recruitment of effector cells, virus control, and immunopathology. Our results indicate that CCR5 and CXCR3 are largely dispensable for tissue infiltration and virus control. In contrast, the T-cell response is accelerated in CCR5(-/-) and CCR5/CXCR3(-/-) mice and the absence of CCR5 is associated with the induction of CD8(+) T-cell-mediated immunopathology consisting of marked hepatic microvesicular steatosis.
U2 - 10.1128/JVI.01242-07
DO - 10.1128/JVI.01242-07
M3 - Journal article
C2 - 17626099
SN - 0022-538X
VL - 81
SP - 10101
EP - 10112
JO - Journal of Virology
JF - Journal of Virology
IS - 18
ER -