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-Induced Inflammatory Responses and Antiviral Defense in Liver1
* Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912; and
Department of Molecular Genetics and Microbiology, The University of Texas, Austin, TX 78712
IFN-
/
-mediated functions promote production of MIP-1 (or CCL3) by mediating the recruitment of MIP-1-producing macrophages to the liver during early infection with murine CMV. These responses are essential for induction of NK cell inflammation and IFN-
delivery to support effective control of local infection. Nevertheless, it remains to be established if additional chemokine functions are regulated by IFN-/ 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-1 during infection and was dependent on IFN-/ effects for induction. Resident F4/80+ liver leukocytes were identified as primary IFN-/ 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-1 and IFN- 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.
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