Matrix metalloproteinase-9-deficient dendritic cells have impaired migration through tracheal epithelial tight junctions
Matrix metalloproteinase-9-deficient dendritic cells have impaired migration through tracheal epithelial tight junctions
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DOI：
10.1165/rcmb.2003-0370oc
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发表时间：
2004-06-01
影响因子：
6.4
通讯作者：
Schneeberger, EE
中科院分区：
文献类型：
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作者：
Ichiyasu, H;McCormack, JM;Schneeberger, EE
当采样吸入抗原时，树突状细胞（DC）必须穿透紧密连接（TJ）屏障，同时保持TJ的密封。在基质金属蛋白酶(MMP)-9缺陷小鼠中，体内实验表明DC向空气空间的迁移受到损害。为了研究潜在的机制，我们用小鼠气管上皮细胞和小鼠骨髓DC （BMDC）建立了一个明确的体外模型。巨噬细胞炎症蛋白(MIP)-1 α或MIP-3 β以时间依赖性的方式诱导转运。对照MMP-9(+/+) BMDC与粒细胞巨噬细胞集落刺激因子培养7 d后，经上皮向mip -3 β的迁移比mip -1 α多30倍，表明DC表型更成熟。在MMP抑制剂GM6001存在下，IVIMP-9(-/-) BMDC和MMP9(+/+) BMDC虽然对mip -3 β表现出类似的偏好，但它们穿过上皮的能力明显受损。然而，CCR5和CCR7在MMP-9（-/-）和MMP9(+/+) BMDC中的表达水平相似。在经上皮迁移前后检测BMDC中完整TJ蛋白occludin和claudin-1的表达。有趣的是，在MMP-9（-/-）和对照BMDC中，occludin而不是claudin-1在经上皮迁移后被降解。此外，与对照BMDC相比，MMP-9（-/-）中claudin-1的表达增加了50倍。这些观察结果表明，occludin和claudin-1受到不同的调控，并提示MMP-9的缺乏可能影响claudin-1的转换。
When sampling inhaled antigens, dendritic cells (DC) must penetrate the tight junction (TJ) barrier while maintaining the TJ seal. In matrix metalloproteinase (MMP)-9-deficient mice, in vivo experiments suggest that migration of DC into air spaces is impaired. To examine the underlying mechanisms, we established a well-defined in vitro model using mouse tracheal epithelial cells and mouse bone marrow DC (BMDC). Transmigration was elicited with either macrophage inflammatory protein (MIP)-1alpha or MIP-3beta in a time-dependent manner. Control MMP-9(+/+) BMDC cultured with granulocyte macrophage-colony-stimulating factor for 7 d showed a 30-fold greater transepithelial migration toward MIP-3beta than MIP-1alpha, indicating a more mature DC phenotype. IVIMP-9(-/-) BMDC as well as MMP9(+/+) BMDC in the presence of the MMP inhibitor GM6001, although showing a similar preference for MIP-3beta, were markedly impaired in their ability to traverse the epithelium. Expression levels of CCR5 and CCR7, however, were similar in both MMP-9(-/-) and MMP9(+/+) BMDC. Expression of the integral TJ proteins, occludin and claudin-1, were examined in BMDC before and after transepithelial migration. Interestingly, occludin but not claudin-1 was degraded following transepithelial migration in both MMP-9(-/-) and control BMDC. In addition, there was a > 2-fold increase in claudin-1 expression in MMP-9(-/-) as compared with control BMDC. These observations indicate that occludin and claudin-1 are differentially regulated and suggest that the lack of MMP-9 may affect claudin-1 turnover.