α-Chain phosphorylation of the human leukocyte CD11b/CD18 (Mac-1) integrin is pivotal for integrin activation to bind ICAMs and leukocyte extravasation
α-Chain phosphorylation of the human leukocyte CD11b/CD18 (Mac-1) integrin is pivotal for integrin activation to bind ICAMs and leukocyte extravasation
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DOI：
10.1182/blood-2006-03-013557
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发表时间：
2006-11-15
期刊：
影响因子：
20.3
通讯作者：
Gahmberg, Carl G.
中科院分区：
文献类型：
--
作者：
Fagerholm, Susanna C.;Varis, Minna;Gahmberg, Carl G.
混杂的 CD11b/CD18 (Mac-1) 整合素在调节许多免疫功能中发挥重要作用，例如通过与内皮配体 ICAM-1 和 ICAM-2 相互作用、iC3b 介导的吞噬作用和细胞凋亡，白细胞粘附和从血流中迁移。然而，人们对 Mac-1 由内而外激活的机制仍然知之甚少。整合素胞质结构域的磷酸化正在成为调节整合素功能的重要机制。在这里，我们研究了人 CD11b 的磷酸化，它发生在中性粒细胞的细胞质 Ser1126 上。我们发现丝氨酸磷酸化位点的突变导致 Mac-1 无法被激活以结合细胞配体 ICAM-1 和 ICAM-2。然而，CD11b 突变细胞完全能够结合其他研究的 CD11b 配体（例如 iC3b 和变性 BSA）。对于突变的整合素，整合素胞外域中表达的激活表位和可溶性 ICAM 配体的亲和力降低。此外，在体外跨内皮测定中，该突变导致趋化因子诱导的迁移受到抑制，并显着减少静脉注射细胞在 Balb/c 小鼠脾脏和肺部的积累。这些结果描述了 Mac-1-整合素激活的一种新的选择性机制，它介导白细胞从血流迁移到组织。
The promiscuous CD11b/CD18 (Mac-1) integrin has important roles in regulating many immunologic functions such as leukocyte adhesion and emigration from the bloodstream via interactions with the endothelial ligands ICAM-1 and ICAM-2, iC3b-mediated phagocytosis, and apoptosis. However, the mechanisms for Mac-1 inside-out activation have remained poorly understood. Phosphorylation of integrin cytoplasmic domains is emerging as an important mechanism of regulating integrin functions. Here, we have studied phosphorylation of human CD11b, which takes place on the cytoplasmic Ser1126 in neutrophils. We show that mutation of the serine phosphorylation site leads to inability of Mac-1 to become activated to bind the cellular ligands ICAM-1 and ICAM-2. However, CD11b-mutant cells are fully capable of binding other studied CD11b ligands (le, iC3b and denatured BSA). Activation epitopes expressed in the extracellular domain of the integrin and affinity for soluble ICAM ligands were decreased for the mutated integrin. Additionally, the mutation resulted in inhibition of chemokine-induced migration in a transendothelial assay in vitro and significantly reduced the accumulation of intravenously administered cells in the spleen and lungs of Balb/c mice. These results characterize a novel selective mechanism of Mac-1-integrin activation, which mediates leukocyte emigration from the bloodstream to the tissues.