title: Monocyte chemoattractant protein-1 and CCR2 interactions are required for IFN-alpha/beta-induced inflammatory responses and antiviral defense in liver.
abstract: IFN-alpha/beta-mediated functions promote production of MIP-1alpha (or CCL3) by mediating the recruitment of MIP-1alpha-producing macrophages to the liver during early infection with murine CMV. These responses are essential for induction of NK cell inflammation and IFN-gamma delivery to support effective control of local infection. Nevertheless, it remains to be established if additional chemokine functions are regulated by IFN-alpha/beta 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-1alpha during infection and was dependent on IFN-alpha/beta effects for induction. Resident F4/80(+) liver leukocytes were identified as primary IFN-alpha/beta 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-1alpha and IFN-gamma 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Hokeness
authors.forename: William A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: Christine A
authors.initials: CA
authors.lastname: Biron
authors.forename: Thais P
authors.initials: TP
authors.lastname: Salazar-Mather
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000821:virology; D007370:Interferon Type I / Q000008:administration & dosage / Q000502:physiology* / Q000627:therapeutic use; D007700:Kinetics; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins; D019562:Viral Load
chemical_list: C515334:CCR2 protein, human; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D007370:Interferon Type I; D019402:Macrophage Inflammatory Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011994:Recombinant Proteins