Murine macrophage TLR2-FcγR synergy via FcγR licensing of IL-6 cytokine mRNA ribosome binding and translation.
Murine macrophage TLR2-FcγR synergy via FcγR licensing of IL-6 cytokine mRNA ribosome binding and translation.
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DOI：
10.1371/journal.pone.0200764
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Drake JR
中科院分区：
文献类型：
--
作者：
Hunt D;Drake LA;Drake JR
巨噬细胞（Macrophages，Mcls）是免疫系统的哨兵，它使用模式识别受体如Toll样受体（TLR）来检测入侵的病原体，并使用免疫受体如FcγR来感知宿主的免疫状态。这两个信号通路之间的串扰允许Mcls调整细胞对主要条件的整体反应。然而，TLR-FcγR串扰的分子机制仅部分了解。因此，我们采用了免疫相关的MCLs刺激物，一种携带TLR 2激动剂但不携带TLR 4激动剂（iBTLR 2）的灭活革兰氏阴性细菌，用单克隆抗体（mAb-iBTLR 2）调理，作为研究FcγR调节TLR 2驱动的IL-6（一种关键炎性细胞因子）产生的工具。我们选择这种特定的激动剂作为研究工具，因为MMP 3响应mAb-iBTLR 2产生任何可检测的IL-6需要TLR 2和FcγR信号传导，使其成为研究受体协同作用的优秀系统。利用遗传学、药理学和免疫学方法，我们证明了小鼠MIL-6对mAb-iBTLR 2的应答需要TLR/NF-κB和FcγR/ITAM信号通路的激活。mAb-iBTLR 2与TLR 2的结合驱动NF-κB活化和IL-6 mRNA的上调，但不能导致IL-6细胞因子的产生/释放。在此，Src家族激酶驱动的FcγR ITAM信号传导是使IL-6 mRNA掺入多聚核糖体和翻译所必需的。这些结果揭示了FcγR ITAM信号传导与TLR信号传导协同作用的新机制，通过“许可”细胞因子mRNA核糖体结合/翻译以驱动强烈的鼠MLR细胞因子应答。
Macrophages (MØs) are sentinels of the immune system that use pattern recognition receptors such as Toll-like receptors (TLR) to detect invading pathogens and immune receptors such as FcγR to sense the host’s immune state. Crosstalk between these two signaling pathways allows the MØ to tailor the cell’s overall response to prevailing conditions. However, the molecular mechanisms underlying TLR-FcγR crosstalk are only partially understood. Therefore, we employed an immunologically-relevant MØ stimulus, an inactivated gram-negative bacterium that bears TLR2 agonists but no TLR4 agonist (iBTLR2) opsonized with a monoclonal antibody (mAb-iBTLR2), as a tool to study FcγR regulation of TLR2-driven production of IL-6, a key inflammatory cytokine. We chose this particular agonist as an investigational tool because MØ production of any detectable IL-6 in response to mAb-iBTLR2 requires both TLR2 and FcγR signaling, making it an excellent system for the study of receptor synergy. Using genetic, pharmacological and immunological approaches, we demonstrate that the murine MØ IL-6 response to mAb-iBTLR2 requires activation of both the TLR/NF-κB and FcγR/ITAM signaling pathways. mAb-iBTLR2 engagement of TLR2 drives NF-κB activation and up-regulation of IL-6 mRNA but fails to result in IL-6 cytokine production/release. Here, Src family kinase-driven FcγR ITAM signaling is necessary to enable IL-6 mRNA incorporation into polysomes and translation. These results reveal a novel mechanism by which FcγR ITAM signaling synergizes with TLR signaling, by “licensing” cytokine mRNA ribosome binding/translation to drive a strong murine MØ cytokine response.
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