Title

Monocyte Chemoattractant Protein-1 and CCR2 Interactions Are Required for IFN-α/β-Induced Inflammatory Responses and Antiviral Defense in Liver

Document Type

Article

Comments

Published by The American Association of Immunologists in the Journal of Immunology, volume 174 no. 3, 2005. Users may access the article here.

Publication Source

Journal of Immunology

Abstract

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.