Bone marrow chimeras and c-fms conditional ablation (Mafia) mice reveal an essential role for resident myeloid cells in lipopolysaccharide/TLR4-induced corneal inflammation.
Bone marrow chimeras and c-fms conditional ablation (Mafia) mice reveal an essential role for resident myeloid cells in lipopolysaccharide/TLR4-induced corneal inflammation.
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DOI：
10.4049/jimmunol.0803505
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发表时间：
2009-03-01
期刊：
影响因子：
--
通讯作者：
Pearlman E
中科院分区：
文献类型：
--
作者：
Chinnery HR;Carlson EC;Sun Y;Lin M;Burnett SH;Perez VL;McMenamin PG;Pearlman E
哺乳动物角膜含有广泛的巨噬细胞和树突状细胞网络。为了确定这些细胞在LPS诱导的角膜炎症中的作用，对TLR 4 −/−小鼠进行亚致死剂量照射，并用来自增强型GFP（eGFP）+/C57 BL/6或eGFP+/TLR 4 −/−小鼠的骨髓细胞重建。刮除角膜上皮，局部加入LPS，24 h后检查角膜基质中的细胞浸润和角膜混浊的发展。发现用C57 BL/6而不是TLR 4 −/−骨髓细胞供体细胞重建的TLR 4 −/−小鼠导致eGFP+细胞浸润到角膜，包括中性粒细胞，并且与盐水处理的角膜相比，角膜混浊也增加。在第二种实验方法中，用LPS刺激转基因巨噬细胞Fas诱导的凋亡（Mafia）小鼠的角膜。这些小鼠在c-fms启动子的控制下表达eGFP和自杀基因，并且用FK 506二聚化剂（AP 20187）全身治疗引起Fas介导的单核细胞凋亡。AP 20187处理的小鼠角膜中的eGFP+细胞显著少于未处理的小鼠。与未处理的对照组相比，在用LPS刺激后，AP 20187处理的小鼠中中性粒细胞募集和角膜混浊的发展受损。此外，LPS在未处理的Mafia小鼠角膜中4 h内诱导CXCL 1/KC和IL-1α产生，这是在细胞浸润之前;然而，AP 20187处理后细胞因子产生受损。总之，来自两种实验方法的结果证明了常驻角膜单核细胞谱系细胞（巨噬细胞和树突状细胞）在角膜炎症发展中的重要作用。
The mammalian cornea contains an extensive network of resident macrophages and dendritic cells. To determine the role of these cells in LPS-induced corneal inflammation, TLR4−/− mice were sublethally irradiated and reconstituted with bone marrow cells from either enhanced GFP (eGFP)+/C57BL/6 or eGFP+/TLR4−/− mice. The corneal epithelium was abraded, LPS was added topically, and cellular infiltration to the corneal stroma and development of corneal haze were examined after 24 h. TLR4−/− mice reconstituted with C57BL/6, but not TLR4−/− bone marrow cells donor cells were found to cause infiltration of eGFP+ cells to the cornea, including neutrophils, and also increased corneal haze compared with saline-treated corneas. In a second experimental approach, corneas of transgenic macrophage Fas induced apoptosis (Mafia) mice were stimulated with LPS. These mice express eGFP and a suicide gene under control of the c-fms promoter, and systemic treatment with the FK506 dimerizer (AP20187) causes Fas-mediated apoptosis of monocytic cells. AP20187-treated mice had significantly fewer eGFP+ cells in the cornea than untreated mice. After stimulation with LPS neutrophil recruitment and development of corneal haze were impaired in AP20187-treated mice compared with untreated controls. Furthermore, LPS induced CXCL1/KC and IL-1α production within 4 h in corneas of untreated Mafia mice, which is before cellular infiltration; however, cytokine production was impaired after AP20187 treatment. Together, results from both experimental approaches demonstrate an essential role for resident corneal monocytic lineage cells (macrophages and dendritic cells) in development of corneal inflammation.
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