Crowley M T, Costello P S, Fitzer-Attas C J, Turner M, Meng F, Lowell C, Tybulewicz V L, DeFranco A L
G.W. Hooper Foundation, University of California, San Francisco, California 94143-0552, USA.
J Exp Med. 1997 Oct 6;186(7):1027-39. doi: 10.1084/jem.186.7.1027.
Receptors on macrophages for the Fc region of IgG (FcgammaR) 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 FcgammaR cross-linking. Macrophages derived from Syk-deficient (Syk-) mice were defective in phagocytosis of particles bound by FcgammaRs, as well as in many FcgammaR-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 FcgammaRs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked FcgammaR-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for FcgammaR-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 FcgammaR engagement, accompanied by a delay in FcgammaR-mediated phagocytosis. These observations demonstrate that Syk is critical for FcgammaR-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 FcgammaR's analogous to models of signaling by the B and T cell antigen receptors.
巨噬细胞上的IgG Fc区受体（FcγR）介导了许多对宿主免疫至关重要的反应。这些反应所需的信号事件可能是在FcγR交联后由Src家族和Syk家族酪氨酸激酶的激活引发的。源自Syk缺陷（Syk-）小鼠的巨噬细胞在吞噬由FcγR结合的颗粒方面存在缺陷，在许多FcγR诱导的信号事件中也存在缺陷，包括一些细胞底物的酪氨酸磷酸化和MAP激酶的激活。相比之下，Syk-巨噬细胞对另一种强大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未受影响。Syk-巨噬细胞表现出形成与通过FcγR与细胞结合的颗粒相对的聚合肌动蛋白结构（肌动蛋白杯），但未能进行内化。有趣的是，磷脂酰肌醇3-激酶抑制剂在此阶段也阻断了FcγR介导的吞噬作用。因此，PI 3-激酶可能参与了对FcγR介导的吞噬作用至关重要的Syk依赖性信号通路。源自这些细胞中表达的Src家族激酶的三个成员Hck、Fgr和Lyn缺陷的小鼠的巨噬细胞，在FcγR结合后Syk激活较差，同时FcγR介导的吞噬作用延迟。这些观察结果表明，Syk对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，我们的发现提供了证据支持FcγR类似于B和T细胞抗原受体信号传导模型的顺序酪氨酸激酶激活模型。
