Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, 02-106, Poland.
Departments of Statistics and Bioengineering, and Program in Systems, Synthetic, and Physical Biology, Rice University, Houston, TX, 77005, USA.
Nat Commun. 2018 Feb 5;9(1):493. doi: 10.1038/s41467-017-02640-8.
The innate immune system processes pathogen-induced signals into cell fate decisions. How information is turned to decision remains unknown. By combining stochastic mathematical modelling and experimentation, we demonstrate that feedback interactions between the IRF3, NF-κB and STAT pathways lead to switch-like responses to a viral analogue, poly(I:C), in contrast to pulse-like responses to bacterial LPS. Poly(I:C) activates both IRF3 and NF-κB, a requirement for induction of IFNβ expression. Autocrine IFNβ initiates a JAK/STAT-mediated positive-feedback stabilising nuclear IRF3 and NF-κB in first responder cells. Paracrine IFNβ, in turn, sensitises second responder cells through a JAK/STAT-mediated positive feedforward pathway that upregulates the positive-feedback components: RIG-I, PKR and OAS1A. In these sensitised cells, the 'live-or-die' decision phase following poly(I:C) exposure is shorter-they rapidly produce antiviral responses and commit to apoptosis. The interlinked positive feedback and feedforward signalling is key for coordinating cell fate decisions in cellular populations restricting pathogen spread.
先天免疫系统将病原体诱导的信号转化为细胞命运决定。信息如何转化为决策尚不清楚。通过结合随机数学建模和实验，我们证明了 IRF3、NF-κB 和 STAT 通路之间的反馈相互作用导致对病毒类似物 poly(I:C)的类似开关的反应，而不是对细菌 LPS 的类似脉冲的反应。Poly(I:C)激活 IRF3 和 NF-κB，这是诱导 IFNβ 表达的要求。自分泌 IFNβ 通过 JAK/STAT 介导的正反馈在第一 responder 细胞中稳定核 IRF3 和 NF-κB。旁分泌 IFNβ 通过 JAK/STAT 介导的正前馈途径反过来使第二 responder 细胞敏感，该途径上调正反馈成分：RIG-I、PKR 和 OAS1A。在这些敏感细胞中，poly(I:C)暴露后的“生或死”决定阶段更短——它们迅速产生抗病毒反应并决定凋亡。在限制病原体传播的细胞群体中，相互关联的正反馈和前馈信号对于协调细胞命运决定至关重要。
