Endothelial CD47 promotes vascular endothelial-cadherin tyrosine phosphorylation and participates in T cell recruitment at sites of inflammation in vivo.
Endothelial CD47 promotes vascular endothelial-cadherin tyrosine phosphorylation and participates in T cell recruitment at sites of inflammation in vivo.
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DOI：
10.4049/jimmunol.1103606
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发表时间：
2012-09-01
期刊：
影响因子：
--
通讯作者：
Luscinskas FW
中科院分区：
文献类型：
--
作者：
Azcutia V;Stefanidakis M;Tsuboi N;Mayadas T;Croce KJ;Fukuda D;Aikawa M;Newton G;Luscinskas FW
在炎症部位，内皮粘附分子结合白细胞并传递跨内皮迁移（TEM）所需的信号。我们以前报道了内皮细胞CD 47和白细胞信号调节蛋白γ（SIRPγ）之间的粘附相互作用调节人T细胞TEM。然而，内皮细胞CD 47在体内T细胞TEM中的作用尚未研究。在这里，CD 47 −/−小鼠在TNF-α诱导炎症的真皮气囊模型中显示出血液T细胞以及中性粒细胞和单核细胞的募集减少。用野生型骨髓（BM）细胞重建CD 47 −/−小鼠并没有恢复白细胞向气囊的募集，这表明内皮CD 47的作用。骨髓嵌合体小鼠发炎的提睾肌微循环活体显微镜检查证实了CD 47 −/−内皮细胞TEM的缺陷。在体外人体系统中，TEM需要HUVEC和T细胞上的CD 47。尽管先前的研究表明CD 47依赖性信号传导需要Gαi偶联途径，但对于内皮CD 47并非如此，因为使Gαi失活的百日咳毒素（PTX）没有抑制作用，而Gαi是T细胞TEM所需的。我们接下来研究了伴随白细胞TEM的内皮CD 47依赖性信号传导事件。抗体诱导的CD 47交联显示了强大的肌动蛋白细胞骨架重组和Src和Pyk-2激酶依赖的VE-钙粘蛋白胞质尾酪氨酸磷酸化。该信号传导对PTX不敏感，表明内皮CD 47信号传导不依赖于Gαi。这些发现表明，内皮细胞CD 47的配体参与触发了内皮细胞中的“由外向内”信号，促进白细胞TEM。
At sites of inflammation, endothelial adhesion molecules bind leukocytes and transmit signals required for transendothelial migration (TEM). We previously reported that adhesive interactions between endothelial cell CD47 and leukocyte Signal Regulatory Proteinγ (SIRPγ) regulate human T-cell TEM. The role of endothelial CD47 in T-cell TEM in vivo, however, has not been explored. Here, CD47−/− mice showed reduced recruitment of blood T-cells as well as neutrophils and monocytes in a dermal air pouch model of TNF-α induced inflammation. Reconstitution of CD47−/− mice with wild type bone marrow (BM) cells did not restore leukocyte recruitment to the air pouch, indicating a role for endothelial CD47. The defect in leukocyte TEM in the CD47−/− endothelium was corroborated by intravital microscopy of inflamed cremaster muscle microcirculation in BM chimera mice. In an in vitro human system, CD47 on both HUVEC and T-cells were required for TEM. Although previous studies showed CD47-dependent signaling required Gαi coupled pathways, this was not the case for endothelial CD47 because pertussis toxin (PTX), which inactivates Gαi, had no inhibitory effect, whereas Gαi was required by the T-cell for TEM. We next investigated the endothelial CD47-dependent signaling events that accompany leukocyte TEM. Antibody-induced crosslinking of CD47 revealed robust actin cytoskeleton reorganization and Src and Pyk-2 kinase dependent tyrosine phosphorylation of the VE-cadherin cytoplasmic tail. This signaling was PTX insensitive suggesting that endothelial CD47 signaling is independent of Gαi. These findings suggest that engagement of endothelial CD47 by its ligands triggers “outside-in” signals in endothelium that facilitate leukocyte TEM.
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DOI：
10.1084/jem.194.4.541
发表时间：
2001-08-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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Taylor PA
DOI：
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发表时间：
1995-04-25
影响因子：
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4.8
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DOI：
10.4049/jimmunol.1200385
发表时间：
2012-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Griffin GK;Newton G;Tarrio ML;Bu DX;Maganto-Garcia E;Azcutia V;Alcaide P;Grabie N;Luscinskas FW;Croce KJ;Lichtman AH
通讯作者：
Lichtman AH