Crane Meredith J, Hokeness-Antonelli Kirsten L, Salazar-Mather Thais P
Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.
J Immunol. 2009 Aug 15;183(4):2810-7. doi: 10.4049/jimmunol.0900205. Epub 2009 Jul 20.
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-alpha/beta 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-alpha 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-alpha/beta-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.
单核细胞/巨噬细胞是小鼠巨细胞病毒（MCMV）感染早期关键的先天性免疫应答细胞。已经确定，炎性单核细胞/巨噬细胞在进入感染组织部位之前，会从骨髓释放到外周血中。我们之前报道了IFN-α/β在促进CCR2介导的单核细胞/巨噬细胞响应MCMV感染而募集到肝脏中的作用。然而，在MCMV感染条件下，支持单核细胞/巨噬细胞从骨髓迁移到外周血的机制尚未阐明。在此，我们证明MCMV感染的CCR2缺陷小鼠的骨髓中单核细胞/巨噬细胞积聚，而循环中的单核细胞/巨噬细胞则显著减少。在MCMV感染小鼠的骨髓和血清中检测到CCR2配体MCP-1、MCP-3和MCP-5。此外，用重组IFN-α在培养中刺激时，未感染小鼠的骨髓白细胞会产生高水平的MCP-1和MCP-5，以及中等水平的MCP-3。我们确定骨髓F4/80(+)细胞是MCP-1、MCP-3和MCP-5的主要产生者。此外，CCR2配体的诱导依赖于IFN-α/β介导的信号和MCMV感染。综上所述，结果揭示了炎性细胞因子在刺激骨髓中F4/80(+)细胞产生CCR2结合趋化因子方面的关键作用，并且表明趋化因子的局部产生在病毒感染期间支持单核细胞/巨噬细胞从骨髓进入血液。
