Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice
Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice
复制标题
DOI：
10.1172/jci119798
复制
发表时间：
1997-11-15
影响因子：
15.9
通讯作者：
Charo, IF
中科院分区：
文献类型：
--
作者：
Boring, L;Gosling, J;Charo, IF
单核细胞趋化蛋白-1(MCP-1)是一种强大的单核细胞激动剂，参与动脉粥样硬化和肉芽肿性肺疾病的发病机制。为了确定MCP-1及其相关家族成员在体内的作用，我们利用胚胎干细胞中的同源重组产生了靶向破坏C-C趋化因子受体2(CCR2)的小鼠，CCR2(-/-)小鼠按预期的孟德尔比例出生并正常发育，对硫代乙二酸酯的反应，腹膜巨噬细胞的募集选择性减少，体外趋化试验，CCR2(-/-)白细胞对单核细胞趋化蛋白-1(MCP-1)的反应不能迁移，用牛分枝杆菌纯化蛋白衍生物(PPD)微珠栓塞预敏小鼠可诱发肉芽肿性肺疾病，与野生型相比，CCR2(-/-)小鼠肉芽肿体积缩小，引流淋巴结中干扰素-γ水平显著降低，CCR2(-/-)小鼠PPD致敏的脾细胞和刀豆蛋白A激活的幼稚脾细胞中干扰素-γ的产生也减少。我们得出结论，CCR2(-/-)小鼠在迟发性超敏反应和Th1型细胞因子的产生方面都存在明显的缺陷，这些数据表明CCR2的激活在调节免疫反应以及招募单核/巨噬细胞到炎症部位具有重要的和意想不到的作用。
Monocyte chemoattractant protein-1 (MCP-1) is a potent agonist for mononuclear leukocytes and has been implicated in the pathogenesis of atherosclerosis and granulomatous lung disease, To determine the role of MCP-1 and related family members in vivo, we used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of C-C chemokine receptor 2 (CCR2), the receptor for MCP-1, CCR2(-/-) mice were born at the expected Mendelian ratios and developed normally, In response to thioglycollate, the recruitment of peritoneal macrophages decreased selectively, In in vitro chemotaxis assays, CCR2(-/-) leukocytes failed to migrate in response to MCP-1, Granulomatous lung disease was induced in presensitized mice by embolization with beads coupled to purified protein derivative (PPD) of Mycobacterium bovis, As compared with wild-type littermates, CCR2(-/-) mice had a decrease in granuloma size accompanied by a dramatic decrease in the level of interferon gamma in the draining lymph nodes, Production of interferon gamma was also decreased in PPD-sensitized splenocytes from CCR2(-/-) mice and in naive splenocytes activated by concanavalin A, We conclude that CCR2(-/-) mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines, These data suggest an important and unexpected role for CCR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.