Extracellular calcium elicits feedforward regulation of the Toll-like receptor-triggered innate immune response
Extracellular calcium elicits feedforward regulation of the Toll-like receptor-triggered innate immune response
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DOI：
10.1038/cmi.2015.59
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发表时间：
2015-08
影响因子：
24.1
通讯作者：
Songqing Tang;Taoyong Chen;Mingjin Yang;Lei Wang;Zhou Yu;Bin Xie;C. Qian;Sheng Xu;Nan Li
中科院分区：
文献类型：
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作者：
Songqing Tang;Taoyong Chen;Mingjin Yang;Lei Wang;Zhou Yu;Bin Xie;C. Qian;Sheng Xu;Nan Li
尽管对toll样受体（Toll-like receptor， TLR）信号的反馈调节的认识不断扩大，但TLR信号对入侵微生物固有反应的前馈调节尚不完全清楚。在这里，我们报道了细胞外钙可以在TLR刺激下协调小GTPases Ras和Ras- proxim- 1 （Rap1）的激活，这有利于巨噬细胞通过前反馈机制激活。我们发现，不同剂量的TLR激动剂可以触发不同水平的细胞因子产生，细胞外钙可以增强细胞因子的产生，但螯合试剂乙二醇四乙酸（EGTA）或基质相互作用分子1 （STIM1）的敲低会削弱细胞因子的产生。在与TLR结合后，gtp结合的Ras水平升高，而gtp结合的Rap1水平降低，这可以通过egta介导的细胞外钙的去除来逆转。此外，我们证明Rap1敲低可以解除EGTA对tlr触发的先天反应的抑制作用。对TLR信号通路的研究表明，细胞外钙可能通过前馈激活细胞外信号调节激酶信号通路来调节TLR反应。我们的数据表明，由stim1操作的钙通道介导的细胞外钙的流入可能传递有关细胞外TLR刺激强度的信息，从而在适当水平上启动先天反应。我们的研究可能为tlr触发的先天免疫反应的前馈调节提供机制见解。
Despite the expanding knowledge on feedback regulation of Toll-like receptor (TLR) signaling, the feedforward regulation of TLR signaling for the proper innate response to invading microbes is not fully understood. Here, we report that extracellular calcium can coordinate the activation of the small GTPases Ras and Ras-proximate-1 (Rap1) upon TLR stimulation which favors activation of macrophages through a feedforward mechanism. We show that different doses of TLR agonists can trigger different levels of cytokine production, which can be potentiated by extracellular calcium but are impaired by the chelating reagent ethylene glycol tetraacetic acid (EGTA) or by knockdown of stromal interaction molecule 1 (STIM1). Upon TLR engagement, GTP-bound Ras levels are increased and GTP-bound Rap1 is decreased, which can be reversed by EGTA-mediated removal of extracellular calcium. Furthermore, we demonstrate that Rap1 knockdown rescues the inhibitory effects of EGTA on the TLR-triggered innate response. Examination of the TLR signaling pathway reveals that extracellular calcium may regulate the TLR response via feedforward activation of the extracellular signal-regulated kinase signaling pathway. Our data suggest that an influx of extracellular calcium, mediated by STIM1-operated calcium channels, may transmit the information about the intensity of extracellular TLR stimuli to initiate innate responses at an appropriate level. Our study may provide mechanistic insight into the feedforward regulation of the TLR-triggered innate immune response.