Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2011 Jan 1;186(1):471-8. doi: 10.4049/jimmunol.1003003. Epub 2010 Dec 3.
West Nile virus (WNV) is a re-emerging pathogen responsible for outbreaks of fatal meningoencephalitis in humans. Previous studies have suggested a protective role for monocytes in a mouse model of WNV infection, but the molecular mechanisms have remained unclear. In this study, we show that genetic deficiency in Ccr2, a chemokine receptor on Ly6c(hi) inflammatory monocytes and other leukocyte subtypes, markedly increases mortality due to WNV encephalitis in C57BL/6 mice; this was associated with a large and selective reduction of Ly6c(hi) monocyte accumulation in the brain. WNV infection in Ccr2(+/+) mice induced a strong and highly selective monocytosis in peripheral blood that was absent in Ccr2(-/-) mice, which in contrast showed sustained monocytopenia. When a 1:1 mixture of Ccr2(+/+) and Ccr2(-/-) donor monocytes was transferred by vein into WNV-infected Ccr2(-/-) recipient mice, monocyte accumulation in the CNS was not skewed toward either component of the mixture, indicating that Ccr2 is not required for trafficking of monocytes from blood to brain. We conclude that Ccr2 mediates highly selective peripheral blood monocytosis during WNV infection of mice and that this is critical for accumulation of monocytes in the brain.
西尼罗河病毒（WNV）是一种重新出现的病原体，可导致人类致命性脑膜脑炎的爆发。先前的研究表明，单核细胞在 WNV 感染的小鼠模型中具有保护作用，但分子机制尚不清楚。在这项研究中，我们表明，CCR2 基因缺失（CCR2 是 Ly6c（hi）炎症性单核细胞和其他白细胞亚型上的趋化因子受体）显著增加了 C57BL/6 小鼠 WNV 脑炎的死亡率；这与 Ly6c（hi）单核细胞在大脑中的大量且选择性减少有关。WNV 感染在 Ccr2（+/+）小鼠中诱导强烈且高度选择性的外周血单核细胞增多症，而在 Ccr2（-/-）小鼠中则不存在，后者则持续出现单核细胞减少症。当 Ccr2（+/+）和 Ccr2（-/-）供体单核细胞以 1:1 的比例通过静脉转移到感染了 WNV 的 Ccr2（-/-）受体小鼠中时，CNS 中的单核细胞积累并没有偏向混合物的任何成分，这表明 Ccr2 不需要单核细胞从血液到大脑的运输。我们得出结论，CCR2 介导了 WNV 感染小鼠时外周血单核细胞的高度选择性增多，这对于单核细胞在大脑中的积累至关重要。
