CCR5 and CXCR3 Are Dispensable for Liver Infiltration, but CCR5 Protects against Virus-Induced T-Cell-Mediated Hepatic Steatosis

Abstract

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.Chemokines play a key role in virus-induced inflammation and virus clearance, acting as regulators of leukocyte trafficking (18,49). Among the chemokine receptors, CCR5 has drawn considerable attention as the main coreceptor for human immunodeficiency virus and CXCR3 is a promising target for antiinflammatory therapeutics (41, 52). Notably, both receptors have been associated with type 1 cytokine T-cell responses and the majority of tissue-infiltrating T cells in several human inflammatory diseases are found to coexpress these receptors (7,42,48). During viral infection, CCR5 and CXCR3 are expressed on NK cells and activated CD4 ϩ and CD8 ϩ T cells and the ligands are generally expressed in virus-infected tissues (30,38,50). Further support for the important role of CCR5 and CXCR3 comes from the existence of virally encoded chemokine receptor antagonists targeting these receptors (23,27). In this context, it is not surprising that CXCR3 or its ligands have been experimentally demonstrated to be important for immune-mediated virus control in the central nervous system (CNS), the lungs, the ovaries, and the islet of Langerhans in the pancreas (9,15,20,26,51). In contrast, despite the suggestive expression patterns, several studies have indicated that CCR5 or CCR5 ligands are less important in antiviral immunity (30, 37). The positive findings suggest a role for CCR5 in macrophage and CD4 ϩ T-cell recruitment, but the receptor appears not to be required for CD8 ϩ T-cell migration except in young mice, in which the immune system has not yet reached full maturity (3, 17). The reason for this difference between the two receptors could lie in a difference in biological redundancy.Thus, several CCR5 ...

CXCR3‐deficiency protects influenza‐infected CCR5‐deficient mice from mortality

“…Nevertheless, CCR5‐deficiency resulted in hyper‐inflammatory responses in our murine model of viral infection similar to that reported by other groups 4, 7, 33, 34. It is not known whether humans with naturally occurring CCR5 null mutations have increased susceptibility to influenza as has been seen for other viral pathogens 40, 41, and this warrants further investigation.…”

“…However, two independent groups have reported spontaneous production of IFN‐γ by CCR5 −/− and CXCR3 −/− /CCR5 −/− CD8 T cells 13, 32. Also, antigen‐specific clonal expansion of T cells and T‐cell‐mediated immunopathology was augmented in CCR5 −/− mice infected with lymphocytic choriomeningitis virus 33, 34. Yurchenko et al .…”

The Role of CXCR3 in the Induction of Primary Biliary Cirrhosis

“…In addition, it was reported that CXCR3 and its ligands contributed to the development of necroinflammatory liver damage and progression towards fibrosis in chronic HCV patients [19–28] and other virus-infected liver diseases [29, 30], which implied the possible involvement of chemokine (IP-10 and MIG)-chemokine receptor (CXCR3) interactions in the pathogenesis of PBC [31, 32]. Although studies in human PBC have shown the presence of CXCR3 + T cells in liver tissues, the contribution of CXCR3 to the recruitment of T cells to these inflamed tissues was not well established.…”

Off-label use of maraviroc in clinical practice

“…[2] Besides HIV infection, CCR5 has been involved in a large number of disorders as described by epidemiological, clinical or basic studies. So, there are good evidences that linked CCR5 to liver diseases (e.g., hepatocellular carcinoma and liver steatosis), [3][4][5][6] autoimmune disorders (e.g., rheumatoid arthritis), [7] pulmonary diseases (e.g., pulmonary arterial hypertension and sarcoidosis), [8,9] organ rejection (e.g., stem cell transplant), [10] malignancies (e.g., colorectal cancer), [11] and vascular diseases (e.g., endothelial dysfunction and atherogenesis). [12,13] Therefore, we wonder if CCR5 antagonist could be an attractive therapeutic option to prevent and/or treat different inflammatory and/or malignant diseases.…”