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Regulation of Inflammatory Monocyte/Macrophage Recruitment from the Bone Marrow during Murine Cytomegalovirus Infection: Role for Type I Interferons in Localized Induction of CCR2 Ligands¹

Meredith J. Crane^*, Kirsten L. Hokeness-Antonelli and Thais P. Salazar-Mather^2,*

^* Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912; and Science and Technology Department, Bryant University, Smithfield, RI 02917

Monocytes/macrophages are critical early innate immune responders during murine CMV (MCMV) infection. It has been established that inflammatory monocyte/macrophages are released from the bone marrow and into the peripheral blood before entry into infected tissue sites. We previously reported a role for IFN-/β in promotion of CCR2-mediated recruitment of monocyte/macrophages into the liver in response to MCMV infection. However, the mechanisms that support the migration of monocyte/macrophages from the bone marrow and into the peripheral blood under conditions of MCMV infection have not been elucidated. Herein, we demonstrate an accumulation of monocyte/macrophages in the bone marrow of MCMV-infected CCR2-deficient mice, whereas circulating monocyte/macrophages are profoundly diminished. The CCR2 ligands MCP-1, MCP-3, and MCP-5 are detected in bone marrow and in serum from MCMV-infected mice. Furthermore, bone marrow leukocytes from naive mice produce high levels of MCP-1 and MCP-5, and moderate levels of MCP-3, when stimulated with recombinant IFN- in culture. We identify bone marrow F4/80⁺ cells as major producers of MCP-1, MCP-3, and MCP-5. Moreover, induction of CCR2 ligands is dependent on IFN-/β-mediated signals and MCMV infection. Taken together, the results reveal a critical role for inflammatory cytokines in stimulating production of CCR2-binding chemokines from F4/80⁺ cells in the bone marrow, and they suggest that local production of chemokines supports monocyte/macrophage egress from the bone marrow into the blood during a virus infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant CA102708 (to T.S.-M.). Meredith Crane is supported by a Nicole Rosenthal Hartnett ’91 Graduate Fellowship.

² Address correspondence and reprint requests to Dr. Thais P. Salazar-Mather, Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Box G-B6, Brown University, Providence, RI 02912. E-mail address: Thais_Mather{at}brown.edu

³ Abbreviations used in this paper: MCMV, murine CMV; WT, wild type; rIFN-, recombinant IFN-; CM, conditioned media.

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