The Interplay of Notch Signaling and STAT3 in TLR-Activated Human Primary Monocytes.
The Interplay of Notch Signaling and STAT3 in TLR-Activated Human Primary Monocytes.
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DOI：
10.3389/fcimb.2018.00241
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发表时间：
2018
影响因子：
5.7
通讯作者：
Heeg K
中科院分区：
文献类型：
--
作者：
Hildebrand D;Uhle F;Sahin D;Krauser U;Weigand MA;Heeg K
高度保守的Notch信号通路主要通过调节发育过程和免疫细胞活性参与免疫。在适应性免疫系统中，Notch级联在T和B分化中的作用得到了很好的研究。相比之下，Notch信号在感染过程中在髓系中的功能和调节还知之甚少。在这里，我们展示了TLR信号，通过内毒素刺激或体外感染各种革兰氏阴性和阳性细菌，刺激人血源性单核细胞中Notch受体配体Delta-like 1(DLL1)的表达和Notch信号。TLR激活通过刺激细胞因子表达和自分泌细胞因子受体介导的信号转导和转录激活因子3(STAT3)间接诱导DLL1。此外，我们揭示了在体外感染过程中，Notch信号和Janus Kinase(JAK)/STAT3通路之间存在一个正反馈环路，其中涉及到Notch增强的IL-6。γ分泌酶抑制剂DAPT抑制Notch信号转导减弱TLR4刺激的核内NF-κB亚基p65的积聚，从而减少内毒素和感染介导的IL-6的产生。IL-6释放减少与STAT3磷酸化减少和依赖STAT3的靶基因程序性死亡配体1(PD-L1)表达减少相关。证实重组可溶性DLL1和Notch激活剂奥沙利铂刺激STAT3磷酸化和免疫抑制PD-L1的表达。因此，我们提出了Notch信号和STAT3之间的双向相互作用，以稳定转录因子的激活，并支持依赖STAT3的髓系细胞向免疫抑制表型的重塑。综上所述，这项研究为了解体外感染期间髓系细胞中Notch调控的复杂网络提供了新的见解。此外，它还表明Notch通过诱导免疫抑制的PD-L1参与稳定TLR介导的STAT3激活和STAT3介导的髓系功能表型的调节。
The highly conserved Notch signaling pathway essentially participates in immunity through regulation of developmental processes and immune cell activity. In the adaptive immune system, the impact of the Notch cascade in T and B differentiation is well studied. In contrast, the function, and regulation of Notch signaling in the myeloid lineage during infection is poorly understood. Here we show that TLR signaling, triggered through LPS stimulation or in vitro infection with various Gram-negative and -positive bacteria, stimulates Notch receptor ligand Delta-like 1 (DLL1) expression and Notch signaling in human blood-derived monocytes. TLR activation induces DLL1 indirectly, through stimulated cytokine expression and autocrine cytokine receptor-mediated signal transducer and activator of transcription 3 (STAT3). Furthermore, we reveal a positive feedback loop between Notch signaling and Janus kinase (JAK)/STAT3 pathway during in vitro infection that involves Notch-boosted IL-6. Inhibition of Notch signaling by γ-secretase inhibitor DAPT impairs TLR4-stimulated accumulation of NF-κB subunits p65 in the nucleus and subsequently reduces LPS- and infection-mediated IL-6 production. The reduced IL-6 release correlates with a diminished STAT3 phosphorylation and reduced expression of STAT3-dependent target gene programmed death-ligand 1 (PD-L1). Corroborating recombinant soluble DLL1 and Notch activator oxaliplatin stimulate STAT3 phosphorylation and expression of immune-suppressive PD-L1. Therefore we propose a bidirectional interaction between Notch signaling and STAT3 that stabilizes activation of the transcription factor and supports STAT3-dependent remodeling of myeloid cells toward an immuno-suppressive phenotype. In summary, the study provides new insights into the complex network of Notch regulation in myeloid cells during in vitro infection. Moreover, it points to a participation of Notch in stabilizing TLR-mediated STAT3 activation and STAT3-mediated modulation of myeloid functional phenotype through induction of immune-suppressive PD-L1.
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影响因子：
15.9
作者：
Ito, Toshihiro;Schaller, Matthew;Kunkel, Steven L.
通讯作者：
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