Distinct microenvironmental cues stimulate divergent TLR4-mediated signaling pathways in macrophages.
Distinct microenvironmental cues stimulate divergent TLR4-mediated signaling pathways in macrophages.
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DOI：
10.1126/scisignal.aaf3596
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发表时间：
2016-08-30
影响因子：
7.3
通讯作者：
Midwood KS
中科院分区：
文献类型：
--
作者：
Piccinini AM;Zuliani-Alvarez L;Lim JM;Midwood KS
巨噬细胞表现出表型可塑性，使它们能够针对不同的威胁协调特定的免疫反应。细菌感染和组织损伤分别释放微生物产物脂多糖和细胞外基质糖蛋白Tenascin-C，两者都激活Toll样受体4(TLR4)。我们发现这两种TLR4配体刺激巨噬细胞中不同的信号通路，导致细胞具有不同的表型。尽管被内毒素或Tenascin-C激活的巨噬细胞表现出一些共同的特征，包括核因子κB的激活、丝裂原激活的蛋白激酶信号和细胞因子的合成，但每个配体刺激不同的细胞因子亚群的产生，并产生不同的磷酸蛋白质组特征。此外，Tenascin-C促进巨噬细胞的生成，巨噬细胞表现出细胞外基质成分的合成和磷酸化增加，而内毒素刺激巨噬细胞的产生，显示出增强的降解基质的能力。这些数据揭示了不同微环境线索激活一个模式识别受体是如何产生具有不同表型的巨噬细胞的。
Macrophages exhibit a phenotypic plasticity that enables them to orchestrate specific immune responses to distinct threats. The microbial product lipopolysaccharide (LPS) and the extracellular matrix glycoprotein tenascin-C are released during bacterial infection and tissue injury, respectively, and both activate Toll-like receptor 4 (TLR4). We found that these two TLR4 ligands stimulated distinct signaling pathways in macrophages, resulting in cells with divergent phenotypes. Although macrophages activated by LPS or tenascin-C displayed some common features, including activation of nuclear factor κB and mitogen-activated protein kinase signaling and cytokine synthesis, each ligand stimulated the production of different subsets of cytokines and generated different phosphoproteomic signatures. Moreover, tenascin-C promoted the generation of macrophages that exhibited increased synthesis and phosphorylation of extracellular matrix components, whereas LPS stimulated the production of macrophages that exhibited an enhanced capacity to degrade the matrix. These data reveal how the activation of one pattern recognition receptor by different microenvironmental cues generates macrophage with distinct phenotypes.