Monocyte Chemoattractant Protein-1 and CCR2 Interactions Are Required for IFN-α/β-Induced Inflammatory Responses and Antiviral Defense in Liver
The American Association of Immunologists, Inc.
Journal of Immunology
IFN-α/β-mediated functions promote production of MIP-1α (or CCL3) by mediating the recruitment of MIP-1α-producing macrophages to the liver during early infection with murine CMV. These responses are essential for induction of NK cell inflammation and IFN-γ delivery to support effective control of local infection. Nevertheless, it remains to be established if additional chemokine functions are regulated by IFN-α/β and/or play intermediary roles in supporting macrophage trafficking. The chemokine MCP-1 (or CCL2) plays a distinctive role in the recruitment of macrophages by predominantly stimulating the CCR2 chemokine receptor. Here, we examine the roles of MCP-1 and CCR2 during murine CMV infection in liver. MCP-1 production preceded that of MIP-1α during infection and was dependent on IFN-α/β effects for induction. Resident F4/80+ liver leukocytes were identified as primary IFN-α/β responders and major producers of MCP-1. Moreover, MCP-1 deficiency was associated with a dramatic reduction in the accumulation of macrophages and NK cells, as well as decreased production of MIP-1α and IFN-γ in liver. These responses were also markedly impaired in mice with a targeted disruption of CCR2. Furthermore, MCP-1- and CCR2-deficient mice exhibited increased viral titers and elevated expression of the liver enzyme alanine aminotransferase in serum. These mice also had widespread virus-induced liver pathology and succumbed to infection. Collectively, these results establish MCP-1 and CCR2 interactions as factors promoting early liver inflammatory responses and define a mechanism for innate cytokines in regulation of chemokine functions critical for effective localized antiviral defenses.