A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages.
A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages.
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DOI：
10.1084/jem.186.7.1027
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发表时间：
1997-10-06
期刊：
影响因子：
--
通讯作者：
DeFranco AL
中科院分区：
文献类型：
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作者：
Crowley MT;Costello PS;Fitzer-Attas CJ;Turner M;Meng F;Lowell C;Tybulewicz VL;DeFranco AL
巨噬细胞上 IgG Fc 区 (FcγR) 的受体介导许多对宿主免疫很重要的反应。这些反应所需的信号转导事件可能是由 FcγR 交联后 Src 家族和 Syk 家族酪氨酸激酶的激活引发的。来自 Syk 缺陷 (Syk−) 小鼠的巨噬细胞在吞噬 FcγR 结合的颗粒方面存在缺陷，并且在许多 FcγR 诱导的信号转导事件中存在缺陷，包括许多细胞底物的酪氨酸磷酸化和 MAP 激酶的激活。相比之下，Syk-巨噬细胞对另一种有效的巨噬细胞刺激物脂多糖表现出正常反应。乳胶珠和大肠杆菌的吞噬作用也不受影响。 Syk-巨噬细胞表现出聚合肌动蛋白结构的形成，与 FcγR（肌动蛋白杯）与细胞结合的颗粒相对，但未能进行内化。有趣的是，磷脂酰肌醇 3-激酶抑制剂也在这一阶段阻断了 FcγR 介导的吞噬作用。因此，PI 3-激酶可能参与对 FcγR 介导的吞噬作用至关重要的 Syk 依赖性信号传导途径。源自缺乏在这些细胞中表达的 Src 激酶家族三个成员（Hck、Fgr 和 Lyn）的小鼠的巨噬细胞，在 FcγR 接合时表现出较差的 Syk 激活，并伴有 FcγR 介导的吞噬作用的延迟。这些观察结果表明 Syk 对于 FcγR 介导的吞噬作用以及巨噬细胞中的信号转导至关重要。此外，我们的研究结果提供了支持 FcγR 连续酪氨酸激酶激活模型的证据，该模型类似于 B 细胞和 T 细胞抗原受体的信号传导模型。
Receptors on macrophages for the Fc region of IgG (FcγR) mediate a number of responses important for host immunity. Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after FcγR cross-linking. Macrophages derived from Syk-deficient (Syk−) mice were defective in phagocytosis of particles bound by FcγRs, as well as in many FcγR-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases. In contrast, Syk− macrophages exhibited normal responses to another potent macrophage stimulus, lipopolysaccharide. Phagocytosis of latex beads and Escherichia coli bacteria was also not affected. Syk− macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by FcγRs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked FcγR-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for FcγR-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family of kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon FcγR engagement, accompanied by a delay in FcγR-mediated phagocytosis. These observations demonstrate that Syk is critical for FcγR-mediated phagocytosis, as well as for signal transduction in macrophages. Additionally, our findings provide evidence to support a model of sequential tyrosine kinase activation by FcγR's analogous to models of signaling by the B and T cell antigen receptors.