Leishmania-derived murine monocyte chemoattractant protein 1 enhances the recruitment of a restrictive population of CC chemokine receptor 2-positive macrophages
Leishmania-derived murine monocyte chemoattractant protein 1 enhances the recruitment of a restrictive population of CC chemokine receptor 2-positive macrophages
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DOI：
10.1128/iai.01314-06
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发表时间：
2007-02-01
影响因子：
3.1
通讯作者：
Mosser, David M.
中科院分区：
文献类型：
--
作者：
Conrad, Sean M.;Strauss-Ayali, Dalit;Mosser, David M.
产生编码鼠趋化因子单核细胞趋化蛋白I（MCP-1）的转基因利什曼原虫寄生虫。这些寄生虫转录MCP-1 mRNA并分泌MCP-1蛋白。与野生型感染的小鼠相比，用这些寄生虫感染BALB/c、C57 BL/6或MCP-1敲除（KO）小鼠导致最小的病变发展，在感染的足、淋巴结和脾脏中具有较少的寄生虫。相比之下，转基因寄生虫在CC趋化因子受体2（CCR 2）KO小鼠中引起相当大的病变，其中寄生虫数量相对较高，表明寄生虫是存活的和健康的，并且病变发展的缺乏是CCR 2依赖的。先前用转基因寄生虫感染小鼠对随后的野生型L。这表明转基因寄生虫是由早期先天免疫反应控制的。与先天免疫一致，从感染转基因寄生虫的小鼠耳朵的细胞的流式细胞术显示，在感染后第7天CCR 2阳性巨噬细胞的数量增加。耳部病变中转基因寄生虫的计数表明寄生虫数量显著减少，这与CCR 2阳性巨噬细胞迁移增加一致。从感染转基因寄生虫的小鼠耳中分离的CCR 2阳性巨噬细胞几乎不含寄生虫。体外研究表明，最佳的寄生虫杀灭需要招募CCR 2阳性巨噬细胞，然后用MCP-1和γ干扰素（IFN-γ）组合刺激。这项工作表明，寄生虫衍生的MCP-1可以招募限制性的CCR 2阳性巨噬细胞进入病变，可以最佳地刺激MCP-1和IFN-γ，以有效地杀死利什曼原虫寄生虫。
Transgenic Leishmania parasites that encode the murine chemokine monocyte chemoattractant protein I (MCP-1) were generated. These parasites transcribed MCP-1 mRNA and secreted MCP-1 protein. Infection of BALB/c, C57BL/6, or MCP-1 knockout (KO) mice with these parasites resulted in minimal lesion development with fewer parasites in the infected foot, lymph node, and spleen compared to wild-type-infected mice. In contrast, transgenic parasites caused substantial lesions with relatively high numbers of parasites in CC chemokine receptor 2 (CCR2) KO mice, indicating that the parasites are viable and healthy and that the lack of lesion development is CCR2 dependent. Prior infection of mice with transgenic parasites offered no protection to subsequent wild-type L. major challenge, suggesting that the transgenic parasites are controlled by an early innate immune response. Consistent with innate immunity, flow cytometry of cells from the ears of mice infected with transgenic parasites revealed an increase in the number of CCR2-positive macrophages by day 7 postinfection. The enumeration of transgenic parasites in ear lesions demonstrated a signiticant reduction in parasite numbers, which coincided with the increased CCR2-positive macrophage migration. CCR2-positive macrophages isolated from ears of mice infected with transgenic parasites contained virtually no parasites. In vitro studies revealed that optimal parasite killing required the recruitment of CCR2-positive macrophages, followed by stimulation with a combination of both MCP-1 and gamma interferon (IFN-gamma). This work suggests that the parasite-derived MCP-1 can recruit a restrictive population of CCR2-positive macrophages into lesions that can be optimally stimulated by MCP-1 and IFN-gamma to efficiently kill Leishmania parasites.