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Mechanisms of inside-out signaling of the high-affinity IgG receptor FcγRI
Science Signaling ( IF 6.7 ) Pub Date : 2018-07-24 , DOI: 10.1126/scisignal.aaq0891
Arianne M. Brandsma 1 , Samantha L. Schwartz 2 , Michael J. Wester 2 , Christopher C. Valley 2 , Gittan L. A. Blezer 1 , Gestur Vidarsson 3 , Keith A. Lidke 4 , Toine ten Broeke 1 , Diane S. Lidke 2 , Jeanette H. W. Leusen 1
Affiliation  

Fc receptors (FcRs) are an important bridge between the innate and adaptive immune system. Fc gamma receptor I (FcγRI; CD64), the high-affinity receptor for immunoglobulin G (IgG), plays roles in inflammation, autoimmune responses, and immunotherapy. Stimulation of myeloid cells with cytokines, such as tumor necrosis factor–α ( TNFα) and interferon-γ ( IFNγ), increases the binding of FcγRI to immune complexes (ICs), such as antibody-opsonized pathogens or tumor cells, through a process known as “inside-out” signaling. Using super-resolution imaging, we found that stimulation of cells with IL-3 also enhanced the clustering of FcγRI both before and after exposure to ICs. This increased clustering was dependent on an intact actin cytoskeleton. We found that chemical inhibition of the activity of the phosphatase PP1 reduced FcγRI inside-out signaling, although the phosphorylation of FcγRI itself was unaffected. Furthermore, the antibody-dependent cytotoxic activity of human neutrophils toward CD20-expressing tumor cells was increased after stimulation with TNFα and IFNγ. These results suggest that nanoscale reorganization of FcγRI, stimulated by cytokine-induced, inside-out signaling, enhances FcγRI cellular effector functions.



中文翻译:

高亲和力IgG受体FcγRI由内而外的信号传导机制

Fc受体(FcR)是先天性和适应性免疫系统之间的重要桥梁。Fcγ受体I(FcγRI; CD64)是免疫球蛋白G(IgG)的高亲和力受体,在炎症,自身免疫反应和免疫疗法中发挥作用。通过一种过程刺激细胞因子(例如肿瘤坏死因子-α(TNFα)和干扰素-γ(IFNγ))的髓样细胞,增加了FcγRI与免疫复合物(ICs)的结合,例如抗体调理的病原体或肿瘤细胞被称为“由内而外”的信令。使用超分辨率成像,我们发现用IL-3刺激细胞还可以增强暴露于IC之前和之后FcγRI的簇集。这种增加的聚集取决于完整的肌动蛋白细胞骨架。我们发现,对磷酸酶PP1的活性进行化学抑制可降低FcγRI由内而外的信号传导,尽管FcγRI本身的磷酸化不受影响。此外,用TNFα和IFNγ刺激后,中性粒细胞对表达CD20的肿瘤细胞的抗体依赖性细胞毒活性增加。这些结果表明,由细胞因子诱导的,由内而外的信号传导刺激的FcγRI纳米级重组增强了FcγRI细胞效应子功能。

更新日期:2018-07-25
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