Cleavage of the CD11b extracellular domain by the leukocyte serprocidins is critical for neutrophil detachment during chemotaxis
Cleavage of the CD11b extracellular domain by the leukocyte serprocidins is critical for neutrophil detachment during chemotaxis
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白细胞 Serprocidins 对 CD11b 胞外结构域的切割对于趋化过程中中性粒细胞脱离至关重要
DOI：
10.1182/blood-2010-05-287722
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发表时间：
2011-05-05
期刊：
影响因子：
20.3
通讯作者：
Liu, Yuan
中科院分区：
文献类型：
--
作者：
Zen, Ke;Guo, Ya-Lan;Liu, Yuan
β(2)-整合素CD11b/CD18介导中性粒细胞(PMN)与上皮单分子层的牢固黏附，这是PMN跨上皮迁移的关键步骤。为了完成迁移过程，附着的PMN必须从上皮单层表面分离才能向前移动。然而，粘附性PMN脱离的机制尚不清楚。在这里，我们提出的证据是，含有配体结合的I结构域的CD11b胞外区被3种结构和功能相关的丝氨酸蛋白(弹性蛋白酶、蛋白酶-3和组织蛋白酶G)切割，这是PMN在初始细胞黏附后分离的一种新机制。动力学研究表明，CD11b的裂解与中性粒细胞脱离和随后的迁移呈正相关。此外，结果表明，弹性蛋白酶、蛋白酶-3和组织蛋白酶G都以类似于中性粒细胞迁移过程中CD11b脱落的方式切割纯化的、具有功能活性的CD11b形式。它们在纯化的CD11b上的切割位点分别位于(761)Thr-Ala(762)(弹性酶/蛋白水解酶-3)和(760)Phe-Thr(761)(组织蛋白酶G)。在弹性蛋白酶/组织蛋白酶G缺陷的BIGE小鼠中，CD11b的裂解和PMN的分离和趋化能力受到损害，这种缺陷可以通过细胞外弹性蛋白酶的加入而修复。通过阐明CD11b通过弹性酶、蛋白酶-3和组织蛋白酶G的脱落作为PMN脱离的新机制，我们的研究为控制炎症提供了新的治疗靶点。(血。2011；117(18)：4885-4894)
The beta(2)-integrin CD11b/CD18 mediates the firm adhesion of neutrophils (PMNs) to epithelial monolayers, a key step in PMN transepithelial migration. To complete the transmigration process, adherent PMNs must detach from epithelial monolayer surfaces to move forward. The mechanism that governs the detachment of adherent PMNs, however, is not clear. Here, we present evidence that cleavage of the CD11b extracellular domain containing the ligand-binding I-domain by 3 structural and functional related serine pro-teases (elastase, proteinase-3 and cathepsin G) serves as a novel mechanism for PMN detachment after the initial cell adhesion. Kinetic studies showed that the cleavage of CD11b is positively correlated with PMN detachment and subsequent transmigration. Moreover, the results demonstrated that elastase, proteinase- 3 and cathepsin G all cleaved the purified, functionally active form of CD11b in a pattern similar to the CD11b shedding that occurs during PMN transmigration. Their cleavage sites on purified CD11b were located at (761)Thr-Ala(762) (elastase/proteinase-3) and (760)Phe-Thr(761) (cathepsin G), respectively. CD11b cleavage and PMN detachment and chemotaxis, were impaired in elastase/cathepsin G-deficient Beige mice; this defect could be restored by the addition of extracellular elastase. By illustrating CD11b shedding by elastase, proteinase-3 and cathepsin G as a novel mechanism for PMN detachment, our study provides novel therapeutic targets for controlling inflammation. (Blood. 2011;117(18):4885-4894)