Impaired lung dendritic cell activation in CCR2 knockout mice
Impaired lung dendritic cell activation in CCR2 knockout mice
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DOI：
10.1016/s0002-9440(10)63380-9
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发表时间：
2004-10-01
影响因子：
6
通讯作者：
Chensue, SW
中科院分区：
文献类型：
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作者：
Chiu, BC;Freeman, CM;Chensue, SW
树突状细胞（DC）募集是抗原（Ag）攻击的肺部的标志性事件。我们之前报道了在 Th1 或 Th2 引发病原体银珠攻击后分析肺部 DC 迁移和激活的模型。为了确定趋化因子在 DC 动员中的作用，我们将此分析应用于 CCR1、CCR2、CCR5 和 CCR6 趋化因子受体敲除小鼠。牛分枝杆菌蛋白 Ag 和蠕虫曼氏血吸虫卵 Ag 均引发多种趋化因子，包括 CCR1、CCR2、CCR5 以及较小程度的 CCR6 配体。来自野生型肺的 DC 表达趋化因子受体 CCR1、CCR2、CCR5 和 CXCR4 的转录物。在所有敲除菌株中，CD11c+ 细胞可能由于受体冗余而被招募到 Ag 珠上。然而，CCR2-/-小鼠中的DC显着降低了MHCII和CD40的表达。这与引流淋巴结培养物中细胞因子产生的消除有关。对局部先天炎症的分析显示，CCR2-/- 小鼠的巨噬细胞募集减少了 50%。混合 CCR2+/+ 绿色荧光蛋白转基因细胞和 CCR2-/- 绿色荧光蛋白阴性细胞的骨髓嵌合体证实 DC 成熟缺陷仅存在于后者群体中。总之，CCR2 敲除赋予了内在的 DC 激活缺陷，CCR2 配体可能促进炎症 DC 的局部激活/成熟。
Dendritic cell (DC) recruitment is a hallmark event in antigen (Ag)-challenged lungs. We previously reported models for analyzing DC migration and activation in the lung after Th1- or Th2-eliciting pathogen Ag-bead challenge. To determine the role of chemokines in DC mobilization, we applied this analysis to CCR1, CCR2, CCR5, and CCR6 chemokine receptor knockout mice. Both Mycobacteria bovis protein Ags and helminthic, Schistosoma mansoni egg Ags, elicited multiple chemokines, including CCR1, CCR2, CCR5, and to a lesser extent CCR6 ligands. DCs from wild-type lungs expressed transcripts for chemokine receptors, CCR1, CCR2, CCR5, and CXCR4. In all knockout strains, CD11c+ cells were recruited to Ag-beads likely because of receptor redundancy. However, DCs in CCR2-/- mice had significantly decreased MHCII and CD40 expression. This was associated with abrogated cytokine production in draining lymph node cultures. Analysis of local innate inflammation revealed a 50% reduction in macrophage recruitment in CCR2-/- mice. Bone marrow chimeras of mixed CCR2+/+ green fluorescent protein transgenic and CCR2-/- green fluorescent protein-negative cells confirmed the DC maturation defect was only among the latter population. In conclusion, CCR2 knockout confers an intrinsic DC activation defect and CCR2 ligands likely promote the local activation/maturation of inflammatory DCs.